Tertiary lymphoid structures as unique constructions associated with the organization, education, and function of tumor-infiltrating immunocytes

Tertiary lymphoid structures as unique constructions associated with the organization, education, and function of tumor-infiltrating immunocytes 三级淋巴结构--影响肿瘤浸润免疫细胞编排、调控及功能的独特结构 1 2 first-author 1 corresp Jian CHEN, zrchenjian@zju.edu.cn Jian CHEN, zrchenjian@zju.edu.cn zrchenjian@zju.edu.cn https://orcid.org/0000-0002-2542-9669 2 3 4 corresp Lie WANG, wanglie@zju.edu.cn Lie WANG, wanglie@zju.edu.cn wanglie@zju.edu.cn https://orcid.org/0000-0001-5094-012X Department of Gastrointestinal Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China Department of Gastrointestinal Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China 浙江大学医学院附属第二医院胃肠外科，中国杭州市，310009 浙江大学医学院附属第二医院胃肠外科，中国杭州市，310009 Institute of Immunology and Bone Marrow Transplantation Center, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China Institute of Immunology and Bone Marrow Transplantation Center, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China 浙江大学医学院免疫研究所及附属第一医院骨髓移植中心，中国杭州市，310003 浙江大学医学院免疫研究所及附属第一医院骨髓移植中心，中国杭州市，310003 Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou 311121, China Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou 311121, China 浙江大学医学中心良渚实验室，中国杭州市，311121 浙江大学医学中心良渚实验室，中国杭州市，311121 Cancer Center, Zhejiang University, Hangzhou 310058, China Cancer Center, Zhejiang University, Hangzhou 310058, China 浙江大学癌症中心，中国杭州市，310058 浙江大学癌症中心，中国杭州市，310058 Tertiary lymphoid structures (TLSs) are formations at sites with persistent inflammatory stimulation, including tumors. These ectopic lymphoid organs mainly consist of chemo-attracting B cells, T cells, and supporting dendritic cells (DCs). Mature TLSs exhibit functional organization for the optimal development and collaboration of adaptive immune response, delivering an augmented effect on the tumor microenvironment (TME). The description of the positive correlation between TLSs and tumor prognosis is reliable only under a certain condition involving the localization and maturation of TLSs. Emerging evidence suggests that underlying mechanisms of the anti-tumor effect of TLSs pave the way for novel immunotherapies. Several approaches have been developed to take advantage of intratumoral TLSs, either by combining it with therapeutic agents or by inducing the neogenesis of TLSs. 三级淋巴结构主要在包括肿瘤在内的慢性炎症部位的非淋巴组织中发展形成。这一异位形成的淋巴结构主要包含趋化因子招募而来的B细胞、T细胞以及起支持作用的树突状细胞（DC）。成熟的三级淋巴结构有利于适应性免疫细胞的发育与互作，进而增强其抗肿瘤免疫应答。但该抗肿瘤效应取决于三级淋巴结构的具体定位以及成熟阶段。目前有越来越多的研究表明三级淋巴结构的抗肿瘤机制将有助于新型免疫疗法的探索。现有的治疗策略研究方案包括联合瘤内三级淋巴结构与药物治疗或诱导瘤内三级淋巴结构的形成，从而实现提升肿瘤治疗疗效和改善肿瘤患者预后的目的。 Tertiary lymphoid structure (TLS) Tumor-infiltrating immunocyte Tumor microenvironment (TME) 三级淋巴结构 肿瘤浸润免疫细胞 肿瘤微环境 1 Introduction 1 Tumor-infiltrating immune cells are key factors that hold the balance of the tumor microenvironment (TME), greatly affecting tumor progression and clinical outcomes ( Giraldo et al., 2019 Giraldo et al., 2019 ; Lei et al., 2020 Lei et al., 2020 ). Numerous attempts have been made to manage tumors by modifying the immune states of the TME, either through immune checkpoint blockade (ICB) on dysfunctional T cells ( Hodi et al., 2010 Hodi et al., 2010 ; Pardoll, 2012 Pardoll, 2012 ) or through the transfusion of ex vivo engineered T cells ( Tran et al., 2016 Tran et al., 2016 ; Gee et al., 2018 Gee et al., 2018 ; Depil et al., 2020 Depil et al., 2020 ). However, emerging evidence indicates that effector cells never fight alone during immune response. Based on their presence in the TME, the localization, organization, and other cell types of the immune cell lineage can all greatly alter the tumor-associated immune response. It is worth pointing out that the compartmentalized organization defined by the physical separation of immune/non-immune clusters could independently determine the outcome of tumor sufferers. Ectopic aggregated but orderly organized immune cells are termed as tertiary lymphoid structures (TLSs) ( Aloisi and Pujol-Borrell, 2006 Aloisi and Pujol-Borrell, 2006 ; Pitzalis et al., 2014 Pitzalis et al., 2014 ), which are representative constructions of the mentioned context. The conspicuous performance of TLSs in tumors has been noticed ( Sautès-Fridman et al., 2019 Sautès-Fridman et al., 2019 ), but the way they contribute to the function of tumor-infiltrating immunocytes by proper organization and education remains poorly understood. Aiming to shape the existing ideas about novel strategies of tumor management, in this paper, we briefly review the composition, organization, and prognostic value of TLSs, as well as the potential mechanism through which they educate tumor-infiltrating immunocytes. 2 Inconsistent immune performance in tumor-associated TLSs 1 The immune cells within the TME have been proved to be key factors in carcinogenesis, tumor progression, and cancer prognosis ( Giraldo et al., 2019 Giraldo et al., 2019 ; Hinshaw and Shevde, 2019 Hinshaw and Shevde, 2019 ; Lei et al., 2020 Lei et al., 2020 ). The existing findings indicate that tumor-antagonizing or tumor-promoting functions are not only restricted to the immune cell types. It has been revealed that the same cell populations might perform opposite functions in certain conditions; however, the reasons for the unpredictability of these tumor-infiltrating immune cells have not been elucidated. Among the various kinds of immune cells, B cells are considered to be the most controversial type. These cells are now recognized as key players in the core immune network, whose quantity could increase at a late tumor stage and result in a dual effect on recurrence and tumor progression ( Bindea et al., 2013 Bindea et al., 2013 ). A comprehensive analysis based on 69 studies covering 19 cancers stated that half of the cases possessed a positive association between tumor-infiltrating B cells (including plasma cells (PCs)) and the clinical outcome, whereas the remainder showed negative (9.3%) or neutral (40.7%) effect ( Wouters and Nelson, 2018 Wouters and Nelson, 2018 ). Since the biases induced by cancer type, pathologic factors, or technical approaches have been removed, the inherent characteristics of the tumor-infiltrating B cells deserve increased attention. The transcriptome and proteomic analysis of ICB-treated melanoma and renal cell carcinoma cohorts revealed unique functional states of B cells in responders, which appeared more memory-like ( Amaria et al., 2018 Amaria et al., 2018 ; Helmink et al., 2020 Helmink et al., 2020 ). A similar paradox was also presented by follicular helper T (Tfh) cells, which robustly predicted breast cancer survival or responsiveness to chemotherapy ( Gu-Trantien et al., 2013 Gu-Trantien et al., 2013 ) but was also reported to be negatively associated with hepatocellular carcinoma (HCC) survival ( Shalapour et al., 2017 Shalapour et al., 2017 ). Additional findings showed that patients with both T and B cells infiltrated into tumors were more likely to possess favorable prognosis than those with only T or only B cells. The co-occurrence of cluster of differentiation 8-positive (CD8 + ) T cells and CD20 + B cells within tumors was found independently associated with improved survival ( Cabrita et al., 2020 Cabrita et al., 2020 ). Moreover, tumor-infiltrating CD8 + T cells, the well accepted positive prognostic factor, only exhibited their cytotoxic capacity and prognostic value if B cells were also augmented within the tumor ( Kroeger et al., 2016 Kroeger et al., 2016 ; Wouters and Nelson, 2018 Wouters and Nelson, 2018 ). Tumors rich in B cells were more likely to be infiltrated with increased levels of naive and memory T cells that were supposed to do well in anti-tumor response ( Cabrita et al., 2020 Cabrita et al., 2020 ). It has been recently acknowledged that immune cells alone are incapable of proper function, as it is their coordinated action that is critical for both the physiological and pathological processes. The complex network of interactions bridges the gaps among diverse immune cells, as well as non-immune cells (Garner and de Visser, 2020). The varied effect of multiple kinds of immunocytes triggered by their co-localization and cooperation reaches the concept of TLSs. These are well-organized aggregates of immune cells in non-lymphoid tissues that are subjected to long-lasting inflammatory response, including chronic infection, autoimmune disease, as well as tumors ( Sautès-Fridman et al., 2019 Sautès-Fridman et al., 2019 ). TLSs are composed of an inner CD20 + B cell-zone mantled with CD3 + T cell-zone, anchored with dendritic cells (DCs) and vessel structure, similar to the lymphoid follicles in secondary lymphoid organs (SLOs) ( Aloisi and Pujol-Borrell, 2006 Aloisi and Pujol-Borrell, 2006 ; Drayton et al., 2006 Drayton et al., 2006 ). TLSs provide an appropriate niche for communication among diverse immune cells. The unencapsulated structure of TLSs enables sufficient interactions between immune cells and the surrounding microenvironment ( Braun et al., 2011 Braun et al., 2011 ). It is reasonable to speculate that the contradictory property of certain immune cells might be attributed to the formation and organization of TLSs to some extent. Supporting evidence shows that only when organized into TLSs, did B cells predict better prognosis and higher response rate to immunotherapy ( Castino et al., 2016 Castino et al., 2016 ; Petitprez et al., 2020 Petitprez et al., 2020 ). B cells outside TLSs are likely to inhibit anti-tumor immunity and contribute to tumor growth ( Germain et al., 2014 Germain et al., 2014 ; Cabrita et al., 2020 Cabrita et al., 2020 ). Similarly, T cells located inside or outside TLSs, or those sporadically infiltrated in tumors without TLSs, showed a distinct transcription signature and molecular phenotype, with the latter group of T cells exhibiting dysfunctional preference ( Cabrita et al., 2020 Cabrita et al., 2020 ). Meanwhile, CXCL13 + CD4 + Tfh cells, one of the major components of TLSs, always indicate extensive immune infiltration within the tumor, intense response to chemotherapy, and longer survival ( Gu-Trantien et al., 2013 Gu-Trantien et al., 2013 ). CXCL13 + CD4 + and CXCL13 + CD8 + T cells could hardly enhance the ICB effect without forming TLSs ( He et al., 2022 He et al., 2022 ). In brief, TLSs facilitate coordinated antitumor response by involving the combined actions of mainly T cells, B cells, and DCs ( Germain et al., 2014 Germain et al., 2014 ; Goc et al., 2014 Goc et al., 2014 ; Carmi et al., 2015 Carmi et al., 2015 ; Kroeger et al., 2016 Kroeger et al., 2016 ). 3 Composition and organization of TLSs in cancer 1 As introduced previously, intratumoral TLSs maintain an active immune response ( Hiraoka et al., 2015 Hiraoka et al., 2015 ). Moreover, the cooperation among the affiliates is well-organized. Although still partly unclear, the current understanding of the generation of TLSs was mostly referred to SLOs considering the anatomical resemblance ( Drayton et al., 2006 Drayton et al., 2006 ). This process is initiated with the colonization of lymphoid tissue inducer (LTi) cells that interact with lymphoid tissue organizer (LTo) cells by lymphotoxin signaling ( de Togni et al., 1994 de Togni et al., 1994 ; Mebius et al., 1997 Mebius et al., 1997 ; Dejardin et al., 2002 Dejardin et al., 2002 ; Yoshida et al., 2002 Yoshida et al., 2002 ; Veiga-Fernandes et al., 2007 Veiga-Fernandes et al., 2007 ). The abovementioned interactions promote the expression of adhesion molecules (e.g., vascular cell adhesion molecule 1 (VCAM1), intercellular adhesion molecule 1 (ICAM1), mucosal vascular addressin cell adhesion molecule 1 (MAdCAM1), and peripheral lymph node addressin (PNAd)) and the production of chemokines (e.g., chemokine (C-C motif) ligand 19 (CCL19), CCL21, and chemokine (C-X-C motif) ligand 13 (CXCL13)), which further leads to vascularization and immune cell recruitment ( Gunn et al., 1998 Gunn et al., 1998 ; Ngo et al., 1999 Ngo et al., 1999 ; Suzuki et al., 1999 Suzuki et al., 1999 ; Ansel et al., 2000 Ansel et al., 2000 ; Luther et al., 2003 Luther et al., 2003 ). However, it has been described that the induction of TLSs was not restricted to lymphotoxin signaling, and several immune cell populations, such as group 3 innate lymphoid cells (ILC3), B cells, T helper 17 (Th17) cells, effector CD8 + T cells, and M1 macrophages, were found to be surrogate LTi cells ( Lochner et al., 2011 Lochner et al., 2011 ; Peters et al., 2011 Peters et al., 2011 ; Guedj et al., 2014 Guedj et al., 2014 ; Carrega et al., 2015 Carrega et al., 2015 ; Peske et al., 2015 Peske et al., 2015 ). Similarly, certain stromal and immune cells were thought to act as potential surrogate LTo cells ( Bénézech et al., 2010 Bénézech et al., 2010 ; Barone et al., 2016 Barone et al., 2016 ; Rodriguez et al., 2021 Rodriguez et al., 2021 ). Even with certain distinctions during the initiation of TLSs and SLOs, the main chemokines involved in the downstream process are shared between these two structures. Among the significant chemokines, CXCL13 performs as a crucial element due to its full participation throughout the TLS organization. As a typical marker of TLSs, the expression of CXCL13 can also be utilized for prognosis prediction. Patients with CXCL13 deletion suffer a significantly higher risk of relapse ( Bindea et al., 2013 Bindea et al., 2013 ). CXCL13, also defined as B lymphocyte chemoattractant, has been proved to be sufficient to mediate B cell recruitment, together with the downstream process for lymphoid neogenesis, including but not limited to vessel differentiation, chemokine induction, T/B segregation, and germinal center (GC) formation ( Luther et al., 2000 Luther et al., 2000 ). Moreover, CXCL13 has also been reported as a unique marker for tumor antigen-specific CD4 + and CD8 + T cells, as well as good prognosis ( Groeneveld et al., 2021 Groeneveld et al., 2021 ; He et al., 2022 He et al., 2022 ). One of the main sources of CXCL13 points to Tfh cells, indispensable in forming extrafollicular and GC responses, where they are crucial for humoral immunity ( Gunn et al., 1998 Gunn et al., 1998 ; Allen et al., 2007 Allen et al., 2007 ; Kerfoot et al., 2011 Kerfoot et al., 2011 ). CXCL13-producing Tfh cells have also been defined as a positive prognostic factor in several tumors, more or less profiting from its promotion for TLS organization ( Gu-Trantien et al., 2013 Gu-Trantien et al., 2013 ; Li et al., 2021 Li et al., 2021 ). In fact, CXCL13-producing antigen-specific Tfh cells, which are necessary and sufficient for TLS formation, effectively dampen colorectal cancer (CRC) development with assistance of B cells ( Overacre-Delgoffe et al., 2021 Overacre-Delgoffe et al., 2021 ). In addition, certain CD8 + T subsets and stromal cells also turned out to be the origin of CXCL13, accompanied by antigen presenting capacity (van de Pavert et al., 2009; Workel et al., 2019 Workel et al., 2019 ; Wu et al., 2020 Wu et al., 2020 ; He et al., 2022 He et al., 2022 ). Interestingly, these CXCL13-producing CD8 + T cells are always recognized as exhausted CD8 + T cells (CD8 + Tex) owing to the highly expressed inhibitory immune checkpoint molecules (such as programmed cell death protein-1 (PD-1), cytotoxic T lymphocyte-associated protein-4 (CTLA-4), T-cell immunoglobulin domain and mucin domain-containing molecule 3 (TIM-3), lymphocyte activation gene-3 (LAG-3), and T cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif (ITIM) domain (TIGIT)) ( Thommen et al., 2018 Thommen et al., 2018 ; Dai et al., 2021 Dai et al., 2021 ; Jin et al., 2021 Jin et al., 2021 ). Unlike the previously accepted poor prognostic value of CD8 + Tex in tumors, the accumulation of CD8 + Tex favors the clinical outcome in CRC, melanoma, and breast cancer, when accompanied with Tfh ( Niogret et al., 2021 Niogret et al., 2021 ). In addition, other chemokines such as CXCL12, CCL19, CCL21, and tumor necrosis factor (TNF) also contribute to lymphoid tissue organogenesis by supporting the infiltration of B cells, T cells, and DCs ( Luther et al., 2002 Luther et al., 2002 ; Furtado et al., 2014 Furtado et al., 2014 ). CCL21 was also shown to be beneficial for the formation of more and larger TLSs ( Luther et al., 2002 Luther et al., 2002 ). Alongside B and T cells that dominate in TLSs, DCs also matter in TLS formation and function. Follicular dendritic cells (FDCs) localized within GC are critical for the selection of memory B cells, while mature dendritic cell-lysosomal-associated membrane proteins (DC-LAMPs; also present as a special marker for tumor-associated TLSs) that are predominantly distributed in the T cell zone act as the major type of antigen-presenting cells (APCs) to facilitate the generation of tumor-reactive T cells ( Wykes et al., 1998 Wykes et al., 1998 ; di Pucchio et al., 2008 di Pucchio et al., 2008 ; Schmitt et al., 2009 Schmitt et al., 2009 ; Goc et al., 2014 Goc et al., 2014 ). DC is generally required for early Tfh differentiation, indicating its indispensable role in the initial step of TLS formation ( Choi et al., 2011 Choi et al., 2011 ; Goenka et al., 2011 Goenka et al., 2011 ; Kato et al., 2015 Kato et al., 2015 ; Krishnaswamy et al., 2017 Krishnaswamy et al., 2017 ). What is more, the formation and maintenance of TLSs are greatly dependent on antigen recognition. As long as the antigens are thoroughly eliminated, TLSs will generally disintegrate ( Geurtsvankessel et al., 2009 Geurtsvankessel et al., 2009 ; Halle et al., 2009 Halle et al., 2009 ). The enrichment of mature DC in TLSs also displayed a potential promotive effect on T cell infiltration, activation, and cytotoxic orientation; moreover, the transmission of CD4 + T cell-derived help signals consequently contributed to long-term survival ( Schoenberger et al., 1998 Schoenberger et al., 1998 ; Yang et al., 2006 Yang et al., 2006 ; Goc et al., 2014 Goc et al., 2014 ; Eickhoff et al., 2015 Eickhoff et al., 2015 ; Hor et al., 2015 Hor et al., 2015 ; Lee et al., 2017 Lee et al., 2017 ; Weinstein et al., 2017 Weinstein et al., 2017 ). 4 Prognostic value of TLSs in cancer 1 Accumulating evidence suggests the magnified anti-tumor immune response in TLSs. Meanwhile, a favorable prognostic and predictive impact of TLSs has been well presented in many kinds of solid tumor ( Sautès-Fridman et al., 2019 Sautès-Fridman et al., 2019 ). Also, the prognostic value of TLSs was found to be independent of tumor stage as well as other survival factors ( Hiraoka et al., 2015 Hiraoka et al., 2015 ; Posch et al., 2018 Posch et al., 2018 ). Studies focusing on tumor ICB therapy have preliminarily revealed the correlation between TLSs and the response to ICB. For multiple tumors including melanoma, CRC, non-small cell lung cancer (NSCLC), and so on, patients with intratumoral TLSs, sometimes featured with enriched B cells or PD-1 hi dysfunctional CD8 + T cells, could better respond to ICB therapy ( Buisseret et al., 2017 Buisseret et al., 2017 ; Johansson-Percival et al., 2017 Johansson-Percival et al., 2017 ; Cabrita et al., 2020 Cabrita et al., 2020 ; Helmink et al., 2020 Helmink et al., 2020 ; Petitprez et al., 2020 Petitprez et al., 2020 ). The biological advantages of TLSs manifest as an increased opportunity for tumor-specific immune cells to encounter the matched antigens. On the other hand, the enhanced immune response benefits from the collaboration among diverse immune cells. It is well known that the fate of Tfh cells, also defined as tumor-specific CD4 + T cells in TME, can be regulated by B cells and B cell-recognized neoantigens. Afterwards, the primed Tfh cells enhance the activation and cytotoxic function of CD8 + T cells by producing interleukin-21 (IL-21) for an anti-tumor effect ( Cui et al., 2021 Cui et al., 2021 ; Niogret et al., 2021 Niogret et al., 2021 ). In turn, the recruitment of Tfh cells is partly due to CXCL13 expression by intratumoral CD8 + T cells ( Niogret et al., 2021 Niogret et al., 2021 ). Furthermore, the sufficient antigen-driven interaction between CD4 + T cells and DC produces CCL3/4 to directly attract CD8 + T cells and increase the possibility of optimal stimulation of antigen-specific CD8 + T cells ( Castellino et al., 2006 Castellino et al., 2006 ). The exact mechanisms for boosting the immune reactivity of TLSs still remain elusive. The prevailing ideas can be roughly summarized into three main groups. (1) Some effector cells are preferred to be recruited into TLSs, such as ILC3 ( Carrega et al., 2015 Carrega et al., 2015 ), natural killer T (NKT) cells ( Bénézech et al., 2015 Bénézech et al., 2015 ), and effective PCs ( Lochner et al., 2011 Lochner et al., 2011 ), which participate in the organization of TLSs. (2) Local priming derived from TLSs orients naive populations to have a particular status, forming the evidence that naive T cells can be attracted into TLSs and maturate into CTLs ( Lee et al., 2006 Lee et al., 2006 ; Garner and de Visser, 2020), and the resident stem-like CD8 + T cells are likely to enter dysfunctional terminal state that can sustain antigen stimulation for the maintenance of TLSs ( Jansen et al., 2019 Jansen et al., 2019 ). Meanwhile, B cells within TLSs are more likely switched into memory B cells, and prefer to maturate toward IgG-producing PCs that boost ICB response by labeling tumor cells with IgG ( Helmink et al., 2020 Helmink et al., 2020 ; Kinker et al., 2021 Kinker et al., 2021 ; Meylan et al., 2022 Meylan et al., 2022 ), and also promoting CD8 + T cells infiltration ( Castino et al., 2016 Castino et al., 2016 ). Without TLSs, however, B cells would function suboptimally and more likely acquire suppressive function ( Siliņa et al., 2018 Siliņa et al., 2018 ; Cillo et al., 2020 Cillo et al., 2020 ; Ruffin et al., 2021 Ruffin et al., 2021 ). It could be interpreted that TLSs-resident B cells are well embraced by T cells and DCs, and protected from immunosuppressive stimuli by tumor cells ( Germain et al., 2014 Germain et al., 2014 ; Siliņa et al., 2018 Siliņa et al., 2018 ; Cabrita et al., 2020 Cabrita et al., 2020 ). (3) Existing effector populations could be reeducated to gain novel characteristics. Th17 cells, one type of surrogate LTi cells, could be induced into Tfh-like population with upregulated CXCL13 expression for TLS induction ( Lochner et al., 2011 Lochner et al., 2011 ; Peters et al., 2011 Peters et al., 2011 ). At the same time, Tfh cells could possess cytotoxic ability as functional Th1-oriented cells under the education of TLSs ( Goc et al., 2014 Goc et al., 2014 ; Noël et al., 2021 Noël et al., 2021 ). Even Tfh cells that locate in distinct sites diverge along their differentiation trajectory, with Tfh outside GC proliferating continuously while GC-resident Tfh stopping proliferation soon after differentiation but performing better in vesicle organization and exocytosis ( Yeh et al., 2022 Yeh et al., 2022 ). The previously defined “dysfunctional” CD8 + Tex cells have been found as a highly proliferative and dynamically differentiating subset in the TME ( Li et al., 2019 Li et al., 2019 ), indicating their unique role in tumor-associated immune response. CD8 + Tex cells always locate within tumor sites thanks to tumor antigen-specific priming, and these cells can be educated by stroma-derived transforming growth factor-β (TGF-β) to secrete Tfh/B cell-recruiting CXCL13 to assist with the formation of TLSs exactly inside tumors ( Workel et al., 2019 Workel et al., 2019 ). On the other hand, the “exhausted” phenotype of CD8 + T cells caused by continuous stimulation could counteract with the help of CD4 + T cells. It has been reported that antigen-activated CD4 + T cells could improve the clonal expansion of effector CD8 + T cells and strengthen tumor-reactive CD8 + T cells by downregulating coinhibitory receptors, increasing migration-related chemokine receptors, and boosting the generation of the cytotoxic effect ( Bennett et al., 1997 Bennett et al., 1997 ; Ridge et al., 1998 Ridge et al., 1998 ; Janssen et al., 2003 Janssen et al., 2003 ; Shedlock and Shen, 2003 Shedlock and Shen, 2003 ; Ahrends et al., 2017 Ahrends et al., 2017 ). As a matter of fact, the composition and function of TLSs vary along with tumor progression, and their presence will not necessarily subvert the immunosuppressive state of the TME, exemplified as highly inflamed tumors ( Sautès-Fridman et al., 2019 Sautès-Fridman et al., 2019 ). There are many factors that determine the phenotype of TLSs, including but not limited to their quantity, location, composition, and degree of maturation. Visually, the morphology of TLSs can differ significantly according to their location, even within the same tumor sample ( Munoz-Erazo et al., 2020 Munoz-Erazo et al., 2020 ), but whether they differ in biological function remains unclear. What is already known is that the location of TLSs is a determinant of their anti-tumor ability. The favorable prognostic value of intratumoral TLSs has been confirmed in HCC, while the adverse effect of tumor-adjacent TLSs has also been established. The tumor margin area is prone to be in an inflamed condition, which potentially alters TLS to become a refuge for tumor stem cells that might cause late recurrence ( Calderaro et al., 2019 Calderaro et al., 2019 ). It is reasonable to presume that not only the density and location, but also the composition and degree of maturation of TLSs could significantly impact their function. Evidence shows that the integration of TLS density and TLS maturation can better predict tumor prognosis than each parameter separately ( Posch et al., 2018 Posch et al., 2018 ). To our knowledge, there are mainly three stages during TLSs maturation. At the initial stage, immature TLSs are segregated aggregates of recruited T and B cells. In the intermediate maturation stage, follicular DCs penetrate into the niches. Finally, GCs are organized within the structure and distinguish mature TLSs. The maturation of TLSs not only affects the activation, proliferation, and affinity maturation of B cells, but also determines the therapeutic response and proggnostic value of TLSs ( Berek et al., 1991 Berek et al., 1991 ; Germain et al., 2014 Germain et al., 2014 ; Siliņa et al., 2018 Siliņa et al., 2018 ). In other words, only TLSs with GCs are active and functional. 5 Clinical application and therapeutic induction of TLSs 1 In view of the given anti-tumor effect of mature TLSs, these fascinating structures could turn into ideal therapeutic targets for a variety of solid tumors. Since it has been well documented that the presence of mature TLSs always predicts better prognosis in the vast majority of solid tumors ( Sautès-Fridman et al., 2019 Sautès-Fridman et al., 2019 ), the strategy for these patients is to make full use of the anti-tumor effect of TLSs. Large clinical cohorts have revealed the positive correlation between TLSs and canonical tumor therapy. Better response to neoadjuvant therapy, which leads to increased pathological complete response, was found to be significantly associated with higher TILs in breast cancer, regardless of the molecular subtypes ( Song et al., 2017 Song et al., 2017 ; Denkert et al., 2018 Denkert et al., 2018 ). The application of ICB in sarcoma, melanoma, and renal cell carcinoma was reinforced by the presence of tumor-associated TLSs ( Cabrita et al., 2020 Cabrita et al., 2020 ; Helmink et al., 2020 Helmink et al., 2020 ; Petitprez et al., 2020 Petitprez et al., 2020 ). With regard to the other group of the patients who lack mature TLSs within the tumor sites, different attempts aiming to trigger the induction of TLSs have been made. Considering that lymphatic vessels are essential for immune cell trafficking, it is reasonable that the major attempts to promote TLS formation began with the induction of high endothelial venules (HEVs) to promote immune infiltration, which has proved feasible ( Jiang, 2020 Jiang, 2020 ). This was achieved by applying lymphotoxin ( Lee et al., 2006 Lee et al., 2006 ; Mounzer et al., 2010 Mounzer et al., 2010 ), vascular targeted LIGHT (an alias for TNF superfamily member 14 (TNFSF14)) ( Johansson-Percival et al., 2017 Johansson-Percival et al., 2017 ), or a combination of antiangiogenesis with programmed death-ligand 1 (PD-L1) blockade ( Allen et al., 2017 Allen et al., 2017 ). HEVs surrounding or passing through TLSs function as gateways for lymphocyte traffic into tumors, as well as scaffolds for lymphoid structure formation ( Martinet et al., 2011 Martinet et al., 2011 ; Asrir et al., 2022 Asrir et al., 2022 ). The existing research shows that a high density of HEVs inside tumors independently assures longer survival and lower risk of relapse ( Martinet et al., 2011 Martinet et al., 2011 ; Bindea et al., 2013 Bindea et al., 2013 ). Besides, the tumor destruction achieved by Treg depletion was partly attributed to the formation of induced HEVs ( Joshi et al., 2015 Joshi et al., 2015 ; Colbeck et al., 2017 Colbeck et al., 2017 ). The above evidence elevates the accessibility and feasibility of targeting HEVs to induce TLS formation for tumor treatment. However, most of these attempts were limited to animal studies; hence additional clinical studies are in urgent need. It is encouraging that progress has been achieved in other clinical trials. Certain patients might benefit from canonical therapy, exemplified by hepatoblastoma patients carrying an adenomatous polyposis coli (APC) germline mutation, who could acquire better prognosis by cisplatin-induced TLSs ( Morcrette et al., 2019 Morcrette et al., 2019 ). In addition, the application of human papillomavirus (HPV) vaccine and allogeneic pancreatic ductal adenocarcinoma vaccine successfully increased the infiltration of effector T cells, which further organized as TLSs to improve survival ( Lutz et al., 2014 Lutz et al., 2014 ; Maldonado et al., 2014 Maldonado et al., 2014 ). It should be noted that, since the potent immune reactivity of TLSs provides their ability to antagonize tumor cells, concomitant autoimmunity should not be overlooked. Limited studies have revealed a risk of lymphocyte leakage for TLS formation caused by ICB therapy. The enrichment of cytotoxic cells within ectopic TLSs led to muscle fiber degeneration, identified as PD-1 myopathy ( Matsubara et al., 2019 Matsubara et al., 2019 ). As a management of autoimmune toxicity caused by immunotherapy, the application of corticosteroids could markedly impair the formation and function of TLSs ( Siliņa et al., 2018 Siliņa et al., 2018 ; van Dijk et al., 2020 van Dijk et al., 2020 ), leaving us with an elaborate risk-benefit ratio that needs careful evaluation. 6 Conclusions and prospects 1 It is beyond doubt that TLSs possess promising prognostic and predictive values in cancers. They provide a chance for various immune cells to be well orchestrated to maximize the immune response ( Fig. 1 Fig. 1 ). Meanwhile, the effect of TLSs acting on tumor-associated immune response is also plausible, which is susceptive to their localization, stage of maturation, and other factors. The flexibility of TLSs also offers us opportunities to manipulate their formation by adjusting certain conditions to achieve the desired therapeutic goal. To this end, a lot of research has been put forward and made preliminary achievements. Follow-up efforts are still needed for a more detailed understanding and a more effective use of tumor-associated TLSs for anticancer therapy. References Ahrends T , Spanjaard A , Pilzecker B , et al. , 2017 . CD4 + T cell help confers a cytotoxic T cell effector program including coinhibitory receptor downregulation and increased tissue invasiveness . Immunity , 47 ( 5 ): 848 - 861.e5 . https://doi.org/10.1016/j.immuni.2017.10.009 https://doi.org/10.1016/j.immuni.2017.10.009 CD4+ T cell help confers a cytotoxic T cell effector program including coinhibitory receptor downregulation and increased tissue invasiveness Allen CDC , Okada T , Tang HL , et al. , 2007 . Imaging of germinal center selection events during affinity maturation . Science , 315 ( 5811 ): 528 - 531 . https://doi.org/10.1126/science.1136736 https://doi.org/10.1126/science.1136736 Imaging of germinal center selection events during affinity maturation Allen E , Jabouille A , Rivera LB , et al. , 2017 . Combined antiangiogenic and anti-PD-L1 therapy stimulates tumor immunity through HEV formation . Sci Transl Med , 9 ( 385 ): eaak9679 . https://doi.org/10.1126/scitranslmed.aak9679 https://doi.org/10.1126/scitranslmed.aak9679 Combined antiangiogenic and anti-PD-L1 therapy stimulates tumor immunity through HEV formation Aloisi F , Pujol-Borrell R , 2006 . Lymphoid neogenesis in chronic inflammatory diseases . Nat Rev Immunol , 6 ( 3 ): 205 - 217 . https://doi.org/10.1038/nri1786 https://doi.org/10.1038/nri1786 Lymphoid neogenesis in chronic inflammatory diseases Amaria RN , Reddy SM , Tawbi HA , et al. , 2018 . Neoadjuvant immune checkpoint blockade in high-risk resectable mela noma. Nat Med , 24 ( 11 ): 1649 - 1654 . https://doi.org/10.1038/s41591-018-0197-1 https://doi.org/10.1038/s41591-018-0197-1 Neoadjuvant immune checkpoint blockade in high-risk resectable mela Ansel KM , Ngo VN , Hyman PL , et al. , 2000 . A chemokine-driven positive feedback loop organizes lymphoid fol A chemokine-driven positive feedback loop organizes lymphoid fol licles . Nature , 406 ( 6793 ): 309 - 314 . https://doi.org/10.1038/35018581 https://doi.org/10.1038/35018581 licles Asrir A , Tardiveau C , Coudert J , et al. , 2022 . Tumor-associated high endothelial venules mediate lymphocyte entry into tumors and predict response to PD-1 plus CTLA-4 combination immunotherapy . Cancer Cell , 40 ( 3 ): 318 - 334.e9 . https://doi.org/10.1016/j.ccell.2022.01.002 https://doi.org/10.1016/j.ccell.2022.01.002 Tumor-associated high endothelial venules mediate lymphocyte entry into tumors and predict response to PD-1 plus CTLA-4 combination immunotherapy Barone F , Gardner DH , Nayar S , et al. , 2016 . Stromal fibroblasts in tertiary lymphoid structures: a novel target in chronic inflammation . Front Immunol , 7 : 477 . https://doi.org/10.3389/fimmu.2016.00477 https://doi.org/10.3389/fimmu.2016.00477 Stromal fibroblasts in tertiary lymphoid structures: a novel target in chronic inflammation Bénézech C , White A , Mader E , et al. , 2010 . Ontogeny of stromal organizer cells during lymph node development . J Immunol , 184 ( 8 ): 4521 - 4530 . https://doi.org/10.4049/jimmunol.0903113 https://doi.org/10.4049/jimmunol.0903113 Ontogeny of stromal organizer cells during lymph node development Bénézech C , Luu NT , Walker JA , et al. , 2015 . Inflammation-induced formation of fat-associated lymphoid clusters . Nat Immunol , 16 ( 8 ): 819 - 828 . https://doi.org/10.1038/ni.3215 https://doi.org/10.1038/ni.3215 Inflammation-induced formation of fat-associated lymphoid clusters Bennett SRM , Carbone FR , Karamalis F , et al. , 1997 . Induction of a CD8 + cytotoxic T lymphocyte response by cross-priming requires cognate CD4 + T cell help . J Exp Med , 186 ( 1 ): 65 - 70 . https://doi.org/10.1084/jem.186.1.65 https://doi.org/10.1084/jem.186.1.65 Induction of a CD8+ cytotoxic T lymphocyte response by cross-priming requires cognate CD4+ T cell help Berek C , Berger A , Apel M , 1991 . Maturation of the immune response in germinal centers . Cell , 67 ( 6 ): 1121 - 1129 . https://doi.org/10.1016/0092-8674(91)90289-b https://doi.org/10.1016/0092-8674(91)90289-b Maturation of the immune response in germinal centers Bindea G , Mlecnik B , Tosolini M , et al. , 2013 . Spatiotemporal dynamics of intratumoral immune cells reveal the immune landscape in human cancer . Immunity , 39 ( 4 ): 782 - 795 . https://doi.org/10.1016/j.immuni.2013.10.003 https://doi.org/10.1016/j.immuni.2013.10.003 Spatiotemporal dynamics of intratumoral immune cells reveal the immune landscape in human cancer Braun A , Worbs T , Moschovakis GL , et al. , 2011 . Afferent lymph-derived T cells and DCs use different chemokine receptor CCR7-dependent routes for entry into the lymph node and intranodal migration . Nat Immunol , 12 ( 9 ): 879 - 887 . https://doi.org/10.1038/ni.2085 https://doi.org/10.1038/ni.2085 Afferent lymph-derived T cells and DCs use different chemokine receptor CCR7-dependent routes for entry into the lymph node and intranodal migration Buisseret L , Garaud S , de Wind A , et al. , 2017 . Tumor-infiltrating lymphocyte composition, organization and PD-1/PD-L1 expression are linked in breast cancer . OncoImmunology , 6 ( 1 ): e1257452 . https://doi.org/10.1080/2162402X.2016.1257452 https://doi.org/10.1080/2162402X.2016.1257452 Tumor-infiltrating lymphocyte composition, organization and PD-1/PD-L1 expression are linked in breast cancer Cabrita R , Lauss M , Sanna A , et al. , 2020 . Tertiary lymphoid structures improve immunotherapy and survival in melanoma . Nature , 577 ( 7791 ): 561 - 565 . https://doi.org/10.1038/s41586-019-1914-8 https://doi.org/10.1038/s41586-019-1914-8 Tertiary lymphoid structures improve immunotherapy and survival in melanoma Calderaro J , Petitprez F , Becht E , et al. , 2019 . Intra-tumoral tertiary lymphoid structures are associated with a low risk of early recurrence of hepatocellular carcinoma . J Hepatol , 70 ( 1 ): 58 - 65 . https://doi.org/10.1016/j.jhep.2018.09.003 https://doi.org/10.1016/j.jhep.2018.09.003 Intra-tumoral tertiary lymphoid structures are associated with a low risk of early recurrence of hepatocellular carcinoma Carmi Y , Spitzer MH , Linde IL , et al. , 2015 . Allogeneic IgG combined with dendritic cell stimuli induce antitumour T-cell immunity . Nature , 521 ( 7550 ): 99 - 104 . https://doi.org/10.1038/nature14424 https://doi.org/10.1038/nature14424 Allogeneic IgG combined with dendritic cell stimuli induce antitumour T-cell immunity Carrega P , Loiacono F , di Carlo E , et al. , 2015 . NCR + ILC3 concentrate in human lung cancer and associate with intratumoral lymphoid structures . Nat Commun , 6 : 8280 . https://doi.org/10.1038/ncomms9280 https://doi.org/10.1038/ncomms9280 NCR+ILC3 concentrate in human lung cancer and associate with intratumoral lymphoid structures Castellino F , Huang AY , Altan-Bonnet G , et al. , 2006 . Chemokines enhance immunity by guiding naive CD8 + T cells to sites of CD4 + T cell-dendritic cell interaction . Nature , 440 ( 7086 ): 890 - 895 . https://doi.org/10.1038/nature04651 https://doi.org/10.1038/nature04651 Chemokines enhance immunity by guiding naive CD8+ T cells to sites of CD4+ T cell-dendritic cell interaction Castino GF , Cortese N , Capretti G , et al. , 2016 . Spatial distribution of B cells predicts prognosis in human pancreatic adenocarcinoma . OncoImmunology , 5 ( 4 ): e1085147 . https://doi.org/10.1080/2162402X.2015.1085147 https://doi.org/10.1080/2162402X.2015.1085147 Spatial distribution of B cells predicts prognosis in human pancreatic adenocarcinoma Choi YS , Kageyama R , Eto D , et al. , 2011 . ICOS receptor instructs T follicular helper cell versus effector cell differentiation via induction of the transcriptional repressor Bcl6 . Immunity , 34 ( 6 ): 932 - 946 . https://doi.org/10.1016/j.immuni.2011.03.023 https://doi.org/10.1016/j.immuni.2011.03.023 ICOS receptor instructs T follicular helper cell versus effector cell differentiation via induction of the transcriptional repressor Bcl6 Cillo AR , Kurten CHL , Tabib T , et al. , 2020 . Immune landscape of viral- and carcinogen-driven head and neck cancer . Immunity , 52 ( 1 ): 183 - 199.e9 . https://doi.org/10.1016/j.immuni.2019.11.014 https://doi.org/10.1016/j.immuni.2019.11.014 Immune landscape of viral- and carcinogen-driven head and neck cancer Colbeck EJ , Jones E , Hindley JP , et al. , 2017 . Treg depletion licenses T cell-driven HEV neogenesis and promotes tumor destruction . Cancer Immunol Res , 5 ( 11 ): 1005 - 1015 . https://doi.org/10.1158/2326-6066.CIR-17-0131 https://doi.org/10.1158/2326-6066.CIR-17-0131 Treg depletion licenses T cell-driven HEV neogenesis and promotes tumor destruction Cui C , Wang JW , Fagerberg E , et al. , 2021 . Neoantigen-driven B cell and CD4 T follicular helper cell collabor ation promotes anti-tumor CD8 T cell responses. Cell , 184 ( 25 ): 6101 - 6118.e13 . https://doi.org/10.1016/j.cell.2021.11.007 https://doi.org/10.1016/j.cell.2021.11.007 Neoantigen-driven B cell and CD4 T follicular helper cell collabor Dai SY , Zeng H , Liu ZP , et al. , 2021 . Intratumoral CXCL 13 +CD8+T cell infiltration determines poor clinical outcomes and immunoevasive contexture in patients with clear cell renal cell carcinoma. J Immunother Cancer , 9 ( 2 ): e001823 . https://doi.org/10.1136/jitc-2020-001823 https://doi.org/10.1136/jitc-2020-001823 Intratumoral CXCL Dejardin E , Droin NM , Delhase M , et al. , 2002 . The lymphotoxin-β receptor induces different patterns of gene expression via two NF-κB pathways . Immunity , 17 ( 4 ): 525 - 535 . https://doi.org/10.1016/s1074-7613(02)00423-5 https://doi.org/10.1016/s1074-7613(02)00423-5 The lymphotoxin-β receptor induces different patterns of gene expression via two NF-κB pathways Denkert C , von Minckwitz G , Darb-Esfahani S , et al. , 2018 . Tumour-infiltrating lymphocytes and prognosis in different subtypes of breast cancer: a pooled analysis of 3771 patients treated with neoadjuvant therapy . Lancet Oncol , 19 ( 1 ): 40 - 50 . https://doi.org/10.1016/S1470-2045(17)30904-X https://doi.org/10.1016/S1470-2045(17)30904-X Tumour-infiltrating lymphocytes and prognosis in different subtypes of breast cancer: a pooled analysis of 3771 patients treated with neoadjuvant therapy Depil S , Duchateau P , Grupp SA , et al. , 2020 . ‘Off-the-shelf’ allogeneic CAR T cells: development and challenges . Nat Rev Drug Discov , 19 ( 3 ): 185 - 199 . https://doi.org/10.1038/s41573-019-0051-2 https://doi.org/10.1038/s41573-019-0051-2 ‘Off-the-shelf’ allogeneic CAR T cells: development and challenges de Togni P , Goellner J , Ruddle NH , et al. , 1994 . Abnormal development of peripheral lymphoid organs in mice deficient in lymphotoxin . Science , 264 ( 5159 ): 703 - 707 . https://doi.org/10.1126/science.8171322 https://doi.org/10.1126/science.8171322 Abnormal development of peripheral lymphoid organs in mice deficient in lymphotoxin di Pucchio T , Chatterjee B , Smed-Sörensen A , et al. , 2008 . Direct proteasome-independent cross-presentation of viral antigen by plasmacytoid dendritic cells on major histocompatibility complex class I . Nat Immunol , 9 ( 5 ): 551 - 557 . https://doi.org/10.1038/ni.1602 https://doi.org/10.1038/ni.1602 Direct proteasome-independent cross-presentation of viral antigen by plasmacytoid dendritic cells on major histocompatibility complex class I Drayton DL , Liao S , Mounzer RH , et al. , 2006 . Lymphoid organ development: from ontogeny to neogenesis . Nat Immunol , 7 ( 4 ): 344 - 353 . https://doi.org/10.1038/ni1330 https://doi.org/10.1038/ni1330 Lymphoid organ development: from ontogeny to neogenesis Eickhoff S , Brewitz A , Gerner MY , et al. , 2015 . Robust anti-viral immunity requires multiple distinct T cell-dendritic cell interactions . Cell , 162 ( 6 ): 1322 - 1337 . https://doi.org/10.1016/j.cell.2015.08.004 https://doi.org/10.1016/j.cell.2015.08.004 Robust anti-viral immunity requires multiple distinct T cell-dendritic cell interactions Furtado GC , Pacer ME , Bongers G , et al. , 2014 . TNFα-dependent development of lymphoid tissue in the absence of RORγt + lymphoid tissue inducer cells . Mucosal Immunol , 7 ( 3 ): 602 - 614 . https://doi.org/10.1038/mi.2013.79 https://doi.org/10.1038/mi.2013.79 TNFα-dependent development of lymphoid tissue in the absence of RORγt+ lymphoid tissue inducer cells Garner H , de Visser KE , 2020 . Immune crosstalk in cancer progression and metastatic spread: a complex conversation . Nat Rev Immunol , 20 ( 8 ): 483 - 497 . https://doi.org/10.1038/s41577-019-0271-z https://doi.org/10.1038/s41577-019-0271-z Immune crosstalk in cancer progression and metastatic spread: a complex conversation Gee MH , Han A , Lofgren SM , et al. , 2018 . Antigen identification for orphan T cell receptors expressed on tumor-infiltrating lymphocytes . Cell , 172 ( 3 ): 549 - 563.e16 . https://doi.org/10.1016/j.cell.2017.11.043 https://doi.org/10.1016/j.cell.2017.11.043 Antigen identification for orphan T cell receptors expressed on tumor-infiltrating lymphocytes Germain C , Gnjatic S , Tamzalit F , et al. , 2014 . Presence of B cells in tertiary lymphoid structures is associated with a protective immunity in patients with lung cancer . Am J Respir Crit Care Med , 189 ( 7 ): 832 - 844 . https://doi.org/10.1164/rccm.201309-1611OC https://doi.org/10.1164/rccm.201309-1611OC Presence of B cells in tertiary lymphoid structures is associated with a protective immunity in patients with lung cancer Geurtsvankessel CH , Willart MAM , Bergen IM , et al. , 2009 . Dendritic cells are crucial for maintenance of tertiary lymphoid structures in the lung of influenza virus-infected mice . J Exp Med , 206 ( 11 ): 2339 - 2349 . https://doi.org/10.1084/jem.20090410 https://doi.org/10.1084/jem.20090410 Dendritic cells are crucial for maintenance of tertiary lymphoid structures in the lung of influenza virus-infected mice Giraldo NA , Sanchez-Salas R , Peske JD , et al. , 2019 . The clinical role of the TME in solid cancer . Br J Cancer , 120 ( 1 ): 45 - 53 . https://doi.org/10.1038/s41416-018-0327-z https://doi.org/10.1038/s41416-018-0327-z The clinical role of the TME in solid cancer Goc J , Germain C , Vo-Bourgais TKD , et al. , 2014 . Dendritic cells in tumor-associated tertiary lymphoid structures signal a Th1 cytotoxic immune contexture and license the positive prognostic value of infiltrating CD8 + T cells . Cancer Res , 74 ( 3 ): 705 - 715 . https://doi.org/10.1158/0008-5472.CAN-13-1342 https://doi.org/10.1158/0008-5472.CAN-13-1342 Dendritic cells in tumor-associated tertiary lymphoid structures signal a Th1 cytotoxic immune contexture and license the positive prognostic value of infiltrating CD8+ T cells Goenka R , Barnett LG , Silver JS , et al. , 2011 . Cutting edge: dendritic cell-restricted antigen presentation initiates the follicular helper T cell program but cannot complete ultim Cutting edge: dendritic cell-restricted antigen presentation initiates the follicular helper T cell program but cannot complete ultim ate effector differentiation . J Immunol , 187 ( 3 ): 1091 - 1095 . https://doi.org/10.4049/jimmunol.1100853 https://doi.org/10.4049/jimmunol.1100853 ate effector differentiation Groeneveld CS , Fontugne J , Cabel L , et al. , 2021 . Tertiary lymphoid structures marker CXCL13 is associated with better survival for patients with advanced-stage bladder cancer treated with immunotherapy . Eur J Cancer , 148 : 181 - 189 . https://doi.org/10.1016/j.ejca.2021.01.036 https://doi.org/10.1016/j.ejca.2021.01.036 Tertiary lymphoid structures marker CXCL13 is associated with better survival for patients with advanced-stage bladder cancer treated with immunotherapy Gu-Trantien C , Loi S , Garaud S , et al. , 2013 . CD4 + follicular helper T cell infiltration predicts breast cancer survival . J Clin Invest , 123 ( 7 ): 2873 - 2892 . https://doi.org/10.1172/JCI67428 https://doi.org/10.1172/JCI67428 CD4+ follicular helper T cell infiltration predicts breast cancer survival Guedj K , Khallou-Laschet J , Clement M , et al. , 2014 . M1 macrophages act as LTβR-independent lymphoid tissue inducer cells during atherosclerosis-related lymphoid neogenesis . Cardiovasc Res , 101 ( 3 ): 434 - 443 . https://doi.org/10.1093/cvr/cvt263 https://doi.org/10.1093/cvr/cvt263 M1 macrophages act as LTβR-independent lymphoid tissue inducer cells during atherosclerosis-related lymphoid neogenesis Gunn MD , Ngo VN , Ansel KM , et al. , 1998 . A B-cell-homing chemokine made in lymphoid follicles activates Burkitt’s lymphoma receptor-1 . Nature , 391 ( 6669 ): 799 - 803 . https://doi.org/10.1038/35876 https://doi.org/10.1038/35876 A B-cell-homing chemokine made in lymphoid follicles activates Burkitt’s lymphoma receptor-1 Halle S , Dujardin HC , Bakocevic N , et al. , 2009 . Induced bronchus-associated lymphoid tissue serves as a general priming site for T cells and is maintained by dendritic cells . J Exp Med , 206 ( 12 ): 2593 - 2601 . https://doi.org/10.1084/jem.20091472 https://doi.org/10.1084/jem.20091472 Induced bronchus-associated lymphoid tissue serves as a general priming site for T cells and is maintained by dendritic cells He JJ , Xiong XX , Yang H , et al. , 2022 . Defined tumor antigen-specific T cells potentiate personalized TCR-T cell therapy and prediction of immunotherapy response . Cell Res , 32 ( 6 ): 530 - 542 . https://doi.org/10.1038/s41422-022-00627-9 https://doi.org/10.1038/s41422-022-00627-9 Defined tumor antigen-specific T cells potentiate personalized TCR-T cell therapy and prediction of immunotherapy response Helmink BA , Reddy SM , Gao JJ , et al. , 2020 . B cells and tertiary lymphoid structures promote immunotherapy response . Nature , 577 ( 7791 ): 549 - 555 . https://doi.org/10.1038/s41586-019-1922-8 https://doi.org/10.1038/s41586-019-1922-8 B cells and tertiary lymphoid structures promote immunotherapy response Hinshaw DC , Shevde LA , 2019 . The tumor microenvironment innately modulates cancer progression . Cancer Res , 79 ( 18 ): 4557 - 4566 . https://doi.org/10.1158/0008-5472.CAN-18-3962 https://doi.org/10.1158/0008-5472.CAN-18-3962 The tumor microenvironment innately modulates cancer progression Hiraoka N , Ino Y , Yamazaki-Itoh R , et al. , 2015 . Intratumoral tertiary lymphoid organ is a favourable prognosticator in patients with pancreatic cancer . Br J Cancer , 112 ( 11 ): 1782 - 1790 . https://doi.org/10.1038/bjc.2015.145 https://doi.org/10.1038/bjc.2015.145 Intratumoral tertiary lymphoid organ is a favourable prognosticator in patients with pancreatic cancer Hodi FS , O'Day SJ , McDermott DF , et al. , 2010 . Improved survival with ipilimumab in patients with metastatic mela noma. N Engl J Med , 363 ( 8 ): 711 - 723 . https://doi.org/10.1056/NEJMoa1003466 https://doi.org/10.1056/NEJMoa1003466 Improved survival with ipilimumab in patients with metastatic mela Hor JL , Whitney PG , Zaid A , et al. , 2015 . Spatiotemporally distinct interactions with dendritic cell subsets facilitates CD4 + and CD8 + T cell activation to localized viral infection . Immunity , 43 ( 3 ): 554 - 565 . https://doi.org/10.1016/j.immuni.2015.07.020 https://doi.org/10.1016/j.immuni.2015.07.020 Spatiotemporally distinct interactions with dendritic cell subsets facilitates CD4+ and CD8+ T cell activation to localized viral infection Jansen CS , Prokhnevska N , Master VA , et al. , 2019 . An intra-tumoral niche maintains and differentiates stem-like CD8 T cells . Nature , 576 ( 7787 ): 465 - 470 . https://doi.org/10.1038/s41586-019-1836-5 https://doi.org/10.1038/s41586-019-1836-5 An intra-tumoral niche maintains and differentiates stem-like CD8 T cells Janssen EM , Lemmens EE , Wolfe T , et al. , 2003 . CD4 + T cells are required for secondary expansion and memory in CD8 + T lymphocytes . Nature , 421 ( 6925 ): 852 - 856 . https://doi.org/10.1038/nature01441 https://doi.org/10.1038/nature01441 CD4+ T cells are required for secondary expansion and memory in CD8+ T lymphocytes Jiang XG , 2020 . Lymphatic vasculature in tumor metastasis and immunobiology . J Zhejiang Univ-Sci B (Biomed & Biotechnol) , 21 ( 1 ): 3 - 11 . https://doi.org/10.1631/jzus.B1800633 https://doi.org/10.1631/jzus.B1800633 Lymphatic vasculature in tumor metastasis and immunobiology Jin KF , Cao YF , Gu Y , et al. , 2021 . Poor clinical outcomes and immunoevasive contexture in CXCL13 + CD8 + T cells enriched gastric cancer patients . OncoImmunology , 10 ( 1 ): 1915560 . https://doi.org/10.1080/2162402X.2021.1915560 https://doi.org/10.1080/2162402X.2021.1915560 Poor clinical outcomes and immunoevasive contexture in CXCL13+CD8+ T cells enriched gastric cancer patients Johansson-Percival A , He B , Li ZJ , et al. , 2017 . De novo induction of intratumoral lymphoid structures and vessel normalization enhances immunotherapy in resistant tumors . Nat Immunol , 18 ( 11 ): 1207 - 1217 . https://doi.org/10.1038/ni.3836 https://doi.org/10.1038/ni.3836 De novo induction of intratumoral lymphoid structures and vessel normalization enhances immunotherapy in resistant tumors Joshi NS , Akama-Garren EH , Lu YS , et al. , 2015 . Regulatory T cells in tumor-associated tertiary lymphoid structures suppress anti-tumor T cell responses . Immunity , 43 ( 3 ): 579 - 590 . https://doi.org/10.1016/j.immuni.2015.08.006 https://doi.org/10.1016/j.immuni.2015.08.006 Regulatory T cells in tumor-associated tertiary lymphoid structures suppress anti-tumor T cell responses Kato Y , Zaid A , Davey GM , et al. , 2015 . Targeting antigen to Clec9A primes follicular Th cell memory responses capable of robust recall . J Immunol , 195 ( 3 ): 1006 - 1014 . https://doi.org/10.4049/jimmunol.1500767 https://doi.org/10.4049/jimmunol.1500767 Targeting antigen to Clec9A primes follicular Th cell memory responses capable of robust recall Kerfoot SM , Yaari G , Patel JR , et al. , 2011 . Germinal center B cell and T follicular helper cell development initiates in the interfollicular zone . Immunity , 34 ( 6 ): 947 - 960 . https://doi.org/10.1016/j.immuni.2011.03.024 https://doi.org/10.1016/j.immuni.2011.03.024 Germinal center B cell and T follicular helper cell development initiates in the interfollicular zone Kinker GS , Vitiello GAF , Ferreira WAS , et al. , 2021 . B cell orchestration of anti-tumor immune responses: a matter of cell localization and communication . Front Cell Dev Biol , 9 : 678127 . https://doi.org/10.3389/fcell.2021.678127 https://doi.org/10.3389/fcell.2021.678127 B cell orchestration of anti-tumor immune responses: a matter of cell localization and communication Krishnaswamy JK , Gowthaman U , Zhang BY , et al. , 2017 . Migratory CD11b + conventional dendritic cells induce T follicular helper cell-dependent antibody responses . Sci Immunol , 2 ( 18 ): eaam9169 . https://doi.org/10.1126/sciimmunol.aam9169 https://doi.org/10.1126/sciimmunol.aam9169 Migratory CD11b+ conventional dendritic cells induce T follicular helper cell-dependent antibody responses Kroeger DR , Milne K , Nelson BH , 2016 . Tumor-infiltrating plasma cells are associated with tertiary lymphoid structures, cytolytic T-cell responses, and superior prognosis in ovarian cancer . Clin Cancer Res , 22 ( 12 ): 3005 - 3015 . https://doi.org/10.1158/1078-0432.CCR-15-2762 https://doi.org/10.1158/1078-0432.CCR-15-2762 Tumor-infiltrating plasma cells are associated with tertiary lymphoid structures, cytolytic T-cell responses, and superior prognosis in ovarian cancer Lee JM , Lee MH , Garon E , et al. , 2017 . Phase I trial of intratumoral injection of CCL21 gene-modified dendritic cells in lung cancer elicits tumor-specific immune responses and CD8 + T-cell infiltration . Clin Cancer Res , 23 ( 16 ): 4556 - 4568 . https://doi.org/10.1158/1078-0432.CCR-16-2821 https://doi.org/10.1158/1078-0432.CCR-16-2821 Phase I trial of intratumoral injection of CCL21 gene-modified dendritic cells in lung cancer elicits tumor-specific immune responses and CD8+ T-cell infiltration Lee Y , Chin RK , Christiansen P , et al. , 2006 . Recruitment and activation of naive T cells in the islets by lymphotoxin β receptor-dependent tertiary lymphoid structure . Immunity , 25 ( 3 ): 499 - 509 . https://doi.org/10.1016/j.immuni.2006.06.016 https://doi.org/10.1016/j.immuni.2006.06.016 Recruitment and activation of naive T cells in the islets by lymphotoxin β receptor-dependent tertiary lymphoid structure Lei X , Lei Y , Li JK , et al. , 2020 . Immune cells within the tumor microenvironment: biological functions and roles in cancer immunotherapy . Cancer Lett , 470 : 126 - 133 . https://doi.org/10.1016/j.canlet.2019.11.009 https://doi.org/10.1016/j.canlet.2019.11.009 Immune cells within the tumor microenvironment: biological functions and roles in cancer immunotherapy Li HJ , van der Leun AM , Yofe I , et al. , 2019 . Dysfunctional CD8 T cells form a proliferative, dynamically regulated compartment within human melanoma . Cell , 176 ( 4 ): 775 - 789.e18 . https://doi.org/10.1016/j.cell.2018.11.043 https://doi.org/10.1016/j.cell.2018.11.043 Dysfunctional CD8 T cells form a proliferative, dynamically regulated compartment within human melanoma Li JP , Wu CY , Chen MY , et al. , 2021 . PD-1 + CXCR5 - CD4 + Th-CXCL13 cell subset drives B cells into tertiary lymphoid structures of nasopharyngeal carcinoma . J Immunother Cancer , 9 ( 7 ): e002101 . https://doi.org/10.1136/jitc-2020-002101 https://doi.org/10.1136/jitc-2020-002101 PD-1+CXCR5-CD4+ Th-CXCL13 cell subset drives B cells into tertiary lymphoid structures of nasopharyngeal carcinoma Lochner M , Ohnmacht C , Presley L , et al. , 2011 . Microbiota-induced tertiary lymphoid tissues aggravate inflammatory disease in the absence of RORγ T and LTi cells . J Exp Med , 208 ( 1 ): 125 - 134 . https://doi.org/10.1084/jem.20100052 https://doi.org/10.1084/jem.20100052 Microbiota-induced tertiary lymphoid tissues aggravate inflammatory disease in the absence of RORγ T and LTi cells Luther SA , Lopez T , Bai W , et al. , 2000 . BLC expression in pancreatic islets causes B cell recruitment and lymphotoxin-dependent lymphoid neogenesis . Immunity , 12 ( 5 ): 471 - 481 . https://doi.org/10.1016/s1074-7613(00)80199-5 https://doi.org/10.1016/s1074-7613(00)80199-5 BLC expression in pancreatic islets causes B cell recruitment and lymphotoxin-dependent lymphoid neogenesis Luther SA , Bidgol A , Hargreaves DC , et al. , 2002 . Differing activities of homeostatic chemokines CCL19, CCL21, and CXCL12 in lymphocyte and dendritic cell recruitment and lymphoid neogenesis . J Immunol , 169 ( 1 ): 424 - 433 . https://doi.org/10.4049/jimmunol.169.1.424 https://doi.org/10.4049/jimmunol.169.1.424 Differing activities of homeostatic chemokines CCL19, CCL21, and CXCL12 in lymphocyte and dendritic cell recruitment and lymphoid neogenesis Luther SA , Ansel KM , Cyster JG , 2003 . Overlapping roles of CXCL13, interleukin 7 receptor α, and CCR7 ligands in lymph node development . J Exp Med , 197 ( 9 ): 1191 - 1198 . https://doi.org/10.1084/jem.20021294 https://doi.org/10.1084/jem.20021294 Overlapping roles of CXCL13, interleukin 7 receptor α, and CCR7 ligands in lymph node development Lutz ER , Wu AA , Bigelow E , et al. , 2014 . Immunotherapy converts nonimmunogenic pancreatic tumors into immunogenic foci of immune regulation . Cancer Immunol Res , 2 ( 7 ): 616 - 631 . https://doi.org/10.1158/2326-6066.CIR-14-0027 https://doi.org/10.1158/2326-6066.CIR-14-0027 Immunotherapy converts nonimmunogenic pancreatic tumors into immunogenic foci of immune regulation Maldonado L , Teague JE , Morrow MP , et al. , 2014 . Intramuscular therapeutic vaccination targeting HPV16 induces T cell responses that localize in mucosal lesions . Sci Transl Med , 6 ( 221 ): 221ra213 . https://doi.org/10.1126/scitranslmed.3007323 https://doi.org/10.1126/scitranslmed.3007323 Intramuscular therapeutic vaccination targeting HPV16 induces T cell responses that localize in mucosal lesions Martinet L , Garrido I , Filleron T , et al. , 2011 . Human solid tumors contain high endothelial venules: association with T- and B-lymphocyte infiltration and favorable prognosis in breast cancer . Cancer Res , 71 ( 17 ): 5678 - 5687 . https://doi.org/10.1158/0008-5472.CAN-11-0431 https://doi.org/10.1158/0008-5472.CAN-11-0431 Human solid tumors contain high endothelial venules: association with T- and B-lymphocyte infiltration and favorable prognosis in breast cancer Matsubara S , Seki M , Suzuki S , et al. , 2019 . Tertiary lymphoid organs in the inflammatory myopathy associated with PD-1 inhibitors . J Immunother Cancer , 7 ( 1 ): 256 . https://doi.org/10.1186/s40425-019-0736-4 https://doi.org/10.1186/s40425-019-0736-4 Tertiary lymphoid organs in the inflammatory myopathy associated with PD-1 inhibitors Mebius RE , Rennert P , Weissman IL , 1997 . Developing lymph nodes collect CD4 + CD3 - LTβ + cells that can differentiate to APC, NK cells, and follicular cells but not T or B cells . Immunity , 7 ( 4 ): 493 - 504 . https://doi.org/10.1016/s1074-7613(00)80371-4 https://doi.org/10.1016/s1074-7613(00)80371-4 Developing lymph nodes collect CD4+CD3-LTβ+ cells that can differentiate to APC, NK cells, and follicular cells but not T or B cells Meylan M , Petitprez F , Becht E , et al. , 2022 . Tertiary lymphoid structures generate and propagate anti-tumor antibody-producing plasma cells in renal cell cancer . Immunity , 55 ( 3 ): 527 - 541.e5 . https://doi.org/10.1016/j.immuni.2022.02.001 https://doi.org/10.1016/j.immuni.2022.02.001 Tertiary lymphoid structures generate and propagate anti-tumor antibody-producing plasma cells in renal cell cancer Morcrette G , Hirsch TZ , Badour E , et al. , 2019 . APC germline hepatoblastomas demonstrate cisplatin-induced intratumor tertiary lymphoid structures . OncoImmunology , 8 ( 6 ): e1583547 . https://doi.org/10.1080/2162402X.2019.1583547 https://doi.org/10.1080/2162402X.2019.1583547 APC germline hepatoblastomas demonstrate cisplatin-induced intratumor tertiary lymphoid structures Mounzer RH , Svendsen OS , Baluk P , et al. , 2010 . Lymphotoxin-alpha contributes to lymphangiogenesis . Blood , 116 ( 12 ): 2173 - 2182 . https://doi.org/10.1182/blood-2009-12-256065 https://doi.org/10.1182/blood-2009-12-256065 Lymphotoxin-alpha contributes to lymphangiogenesis Munoz-Erazo L , Rhodes JL , Marion VC , et al. , 2020 . Tertiary lymphoid structures in cancer—considerations for patient prognosis . Cell Mol Immunol , 17 ( 6 ): 570 - 575 . https://doi.org/10.1038/s41423-020-0457-0 https://doi.org/10.1038/s41423-020-0457-0 Tertiary lymphoid structures in cancer—considerations for patient prognosis Ngo VN , Korner H , Gunn MD , et al. , 1999 . Lymphotoxin α/β and tumor necrosis factor are required for stromal cell expression of homing chemokines in B and T cell areas of the spleen . J Exp Med , 189 ( 2 ): 403 - 412 . https://doi.org/10.1084/jem.189.2.403 https://doi.org/10.1084/jem.189.2.403 Lymphotoxin α/β and tumor necrosis factor are required for stromal cell expression of homing chemokines in B and T cell areas of the spleen Niogret J , Berger H , Rebe C , et al. , 2021 . Follicular helper-T cells restore CD8 + -dependent antitumor immunity and anti-PD-L1/PD-1 efficacy . J Immunother Cancer , 9 ( 6 ): e002157 . https://doi.org/10.1136/jitc-2020-002157 https://doi.org/10.1136/jitc-2020-002157 Follicular helper-T cells restore CD8+-dependent antitumor immunity and anti-PD-L1/PD-1 efficacy Noël G , Fontsa ML , Garaud S , et al. , 2021 . Functional Th1-oriented T follicular helper cells that infiltrate human breast cancer promote effective adaptive immunity . J Clin Invest , 131 ( 19 ): e139905 . https://doi.org/10.1172/JCI139905 https://doi.org/10.1172/JCI139905 Functional Th1-oriented T follicular helper cells that infiltrate human breast cancer promote effective adaptive immunity Overacre-Delgoffe AE , Bumgarner HJ , Cillo AR , et al. , 2021 . Microbiota-specific T follicular helper cells drive tertiary lymphoid structures and anti-tumor immunity against colorectal cancer . Immunity , 54 ( 12 ): 2812 - 2824.e4 . https://doi.org/10.1016/j.immuni.2021.11.003 https://doi.org/10.1016/j.immuni.2021.11.003 Microbiota-specific T follicular helper cells drive tertiary lymphoid structures and anti-tumor immunity against colorectal cancer Pardoll DM , 2012 . The blockade of immune checkpoints in cancer immunotherapy . Nat Rev Cancer , 12 ( 4 ): 252 - 264 . https://doi.org/10.1038/nrc3239 https://doi.org/10.1038/nrc3239 The blockade of immune checkpoints in cancer immunotherapy Peske JD , Thompson ED , Gemta L , et al. , 2015 . Effector lymphocyte-induced lymph node-like vasculature enables naive T-cell entry into tumours and enhanced anti-tumour immunity . Nat Commun , 6 : 7114 . https://doi.org/10.1038/ncomms8114 https://doi.org/10.1038/ncomms8114 Effector lymphocyte-induced lymph node-like vasculature enables naive T-cell entry into tumours and enhanced anti-tumour immunity Peters A , Pitcher LA , Sullivan JM , et al. , 2011 . Th17 cells induce ectopic lymphoid follicles in central nervous system tissue inflammation . Immunity , 35 ( 6 ): 986 - 996 . https://doi.org/10.1016/j.immuni.2011.10.015 https://doi.org/10.1016/j.immuni.2011.10.015 Th17 cells induce ectopic lymphoid follicles in central nervous system tissue inflammation Petitprez F , de Reyniès A , Keung EZ , et al. , 2020 . B cells are associated with survival and immunotherapy response in sarcoma . Nature , 577 ( 7791 ): 556 - 560 . https://doi.org/10.1038/s41586-019-1906-8 https://doi.org/10.1038/s41586-019-1906-8 B cells are associated with survival and immunotherapy response in sarcoma Pitzalis C , Jones GW , Bombardieri M , et al. , 2014 . Ectopic lymphoid-like structures in infection, cancer and autoimmunity . Nat Rev Immunol , 14 ( 7 ): 447 - 462 . https://doi.org/10.1038/nri3700 https://doi.org/10.1038/nri3700 Ectopic lymphoid-like structures in infection, cancer and autoimmunity Posch F , Silina K , Leibl S , et al. , 2018 . Maturation of tertiary lymphoid structures and recurrence of stage II and III colorectal cancer . OncoImmunology , 7 ( 2 ): e1378844 . https://doi.org/10.1080/2162402X.2017.1378844 https://doi.org/10.1080/2162402X.2017.1378844 Maturation of tertiary lymphoid structures and recurrence of stage II and III colorectal cancer Ridge JP , di Rosa F , Matzinger P , 1998 . A conditioned dendritic cell can be a temporal bridge between a CD4 + T-helper and a T-killer cell . Nature , 393 ( 6684 ): 474 - 478 . https://doi.org/10.1038/30989 https://doi.org/10.1038/30989 A conditioned dendritic cell can be a temporal bridge between a CD4+ T-helper and a T-killer cell Rodriguez AB , Peske JD , Woods AN , et al. , 2021 . Immune mechanisms orchestrate tertiary lymphoid structures in tumors via cancer-associated fibroblasts . Cell Rep , 36 ( 3 ): 109422 . https://doi.org/10.1016/j.celrep.2021.109422 https://doi.org/10.1016/j.celrep.2021.109422 Immune mechanisms orchestrate tertiary lymphoid structures in tumors via cancer-associated fibroblasts Ruffin AT , Cillo AR , Tabib T , et al. , 2021 . B cell signatures and tertiary lymphoid structures contribute to outcome in head and neck squamous cell carcinoma . Nat Commun , 12 : 3349 . https://doi.org/10.1038/s41467-021-23355-x https://doi.org/10.1038/s41467-021-23355-x B cell signatures and tertiary lymphoid structures contribute to outcome in head and neck squamous cell carcinoma Sautès-Fridman C , Petitprez F , Calderaro J , et al. , 2019 . Tertiary lymphoid structures in the era of cancer immunotherapy . Nat Rev Cancer , 19 ( 6 ): 307 - 325 . https://doi.org/10.1038/s41568-019-0144-6 https://doi.org/10.1038/s41568-019-0144-6 Tertiary lymphoid structures in the era of cancer immunotherapy Schmitt N , Morita R , Bourdery L , et al. , 2009 . Human dendritic cells induce the differentiation of interleukin-21-producing T follicular helper-like cells through interleukin-12 . Immunity , 31 ( 1 ): 158 - 169 . https://doi.org/10.1016/j.immuni.2009.04.016 https://doi.org/10.1016/j.immuni.2009.04.016 Human dendritic cells induce the differentiation of interleukin-21-producing T follicular helper-like cells through interleukin-12 Schoenberger SP , Toes REM , van der Voort EIH , et al. , 1998 . T-cell help for cytotoxic T lymphocytes is mediated by CD40‒CD40L interactions . Nature , 393 ( 6684 ): 480 - 483 . https://doi.org/10.1038/31002 https://doi.org/10.1038/31002 T-cell help for cytotoxic T lymphocytes is mediated by CD40‒CD40L interactions Shalapour S , Lin XJ , Bastian IN , et al. , 2017 . Inflammation-induced IgA + cells dismantle anti-liver cancer immunity . Nature , 551 ( 7680 ): 340 - 345 . https://doi.org/10.1038/nature24302 https://doi.org/10.1038/nature24302 Inflammation-induced IgA+ cells dismantle anti-liver cancer immunity Shedlock DJ , Shen H , 2003 . Requirement for CD4 T cell help in generating functional CD8 T cell memory . Science , 300 ( 5617 ): 337 - 339 . https://doi.org/10.1126/science.1082305 https://doi.org/10.1126/science.1082305 Requirement for CD4 T cell help in generating functional CD8 T cell memory Siliņa K , Soltermann A , Attar FM , et al. , 2018 . Germinal centers determine the prognostic relevance of tertiary lymphoid structures and are impaired by corticosteroids in lung squamous cell carcinoma . Cancer Res , 78 ( 5 ):‍ 1308 - 1320 . https://doi.org/10.1158/0008-5472.CAN-17-1987 https://doi.org/10.1158/0008-5472.CAN-17-1987 Germinal centers determine the prognostic relevance of tertiary lymphoid structures and are impaired by corticosteroids in lung squamous cell carcinoma Song IH , Heo SH , Bang WS , et al. , 2017 . Predictive value of tertiary lymphoid structures assessed by high endothelial venule counts in the neoadjuvant setting of triple-negative breast cancer . Cancer Res Treat , 49 ( 2 ): 399 - 407 . https://doi.org/10.4143/crt.2016.215 https://doi.org/10.4143/crt.2016.215 Predictive value of tertiary lymphoid structures assessed by high endothelial venule counts in the neoadjuvant setting of triple-negative breast cancer Suzuki G , Sawa H , Kobayashi Y , et al. , 1999 . Pertussis toxin-sensitive signal controls the trafficking of thymocytes across the corticomedullary junction in the thymus . J Immunol , 162 ( 10 ): 5981 - 5985 . Pertussis toxin-sensitive signal controls the trafficking of thymocytes across the corticomedullary junction in the thymus Thommen DS , Koelzer VH , Herzig P , et al. , 2018 . A transcriptionally and functionally distinct PD-1 + CD8 + T cell pool with predictive potential in non-small-cell lung cancer treated with PD-1 blockade . Nat Med , 24 ( 7 ): 994 - 1004 . https://doi.org/10.1038/s41591-018-0057-z https://doi.org/10.1038/s41591-018-0057-z A transcriptionally and functionally distinct PD-1+ CD8+ T cell pool with predictive potential in non-small-cell lung cancer treated with PD-1 blockade Tran E , Robbins PF , Lu YC , et al. , 2016 . T-cell transfer therapy targeting mutant KRAS in cancer . N Engl J Med , 375 ( 23 ): 2255 - 2262 . https://doi.org/10.1056/NEJMoa1609279 https://doi.org/10.1056/NEJMoa1609279 T-cell transfer therapy targeting mutant KRAS in cancer van de Pavert SA , Olivier BJ , Goverse G , et al. , 2009 . Chemokine CXCL13 is essential for lymph node initiation and is induced by retinoic acid and neuronal stimulation . Nat Immunol , 10 ( 11 ): 1193 - 1199 . https://doi.org/10.1038/ni.1789 https://doi.org/10.1038/ni.1789 Chemokine CXCL13 is essential for lymph node initiation and is induced by retinoic acid and neuronal stimulation van Dijk N , Gil-Jimenez A , Silina K , et al. , 2020 . Preoperative ipilimumab plus nivolumab in locoregionally advanced urothelial cancer: the NABUCCO trial . Nat Med , 26 ( 12 ): 1839 - 1844 . https://doi.org/10.1038/s41591-020-1085-z https://doi.org/10.1038/s41591-020-1085-z Preoperative ipilimumab plus nivolumab in locoregionally advanced urothelial cancer: the NABUCCO trial Veiga-Fernandes H , Coles MC , Foster KE , et al. , 2007 . Tyrosine kinase receptor RET is a key regulator of Peyer’s Patch organogenesis . Nature , 446 ( 7135 ): 547 - 551 . https://doi.org/10.1038/nature05597 https://doi.org/10.1038/nature05597 Tyrosine kinase receptor RET is a key regulator of Peyer’s Patch organogenesis Weinstein AM , Chen L , Brzana EA , et al. , 2017 . Tbet and IL-36γ cooperate in therapeutic DC-mediated promotion of ectopic lymphoid organogenesis in the tumor microenvironment . OncoImmunology , 6 ( 6 ): e1322238 . https://doi.org/10.1080/2162402X.2017.1322238 https://doi.org/10.1080/2162402X.2017.1322238 Tbet and IL-36γ cooperate in therapeutic DC-mediated promotion of ectopic lymphoid organogenesis in the tumor microenvironment Workel HH , Lubbers JM , Arnold R , et al. , 2019 . A transcriptionally distinct CXCL13 + CD103 + CD8 + T-cell population is associated with B-cell recruitment and neoantigen load in human cancer . Cancer Immunol Res , 7 ( 5 ): 784 - 796 . https://doi.org/10.1158/2326-6066.CIR-18-0517 https://doi.org/10.1158/2326-6066.CIR-18-0517 A transcriptionally distinct CXCL13+CD103+CD8+ T-cell population is associated with B-cell recruitment and neoantigen load in human cancer Wouters MCA , Nelson BH , 2018 . Prognostic significance of tumor-infiltrating B cells and plasma cells in human cancer . Clin Cancer Res , 24 ( 24 ): 6125 - 6135 . https://doi.org/10.1158/1078-0432.CCR-18-1481 https://doi.org/10.1158/1078-0432.CCR-18-1481 Prognostic significance of tumor-infiltrating B cells and plasma cells in human cancer Wu SZ , Roden DL , Wang CF , et al. , 2020 . Stromal cell diversity associated with immune evasion in human triple-negative breast cancer . EMBO J , 39 ( 19 ): e104063 . https://doi.org/10.15252/embj.2019104063 https://doi.org/10.15252/embj.2019104063 Stromal cell diversity associated with immune evasion in human triple-negative breast cancer Wykes M , Pombo A , Jenkins C , et al. , 1998 . Dendritic cells interact directly with naive B lymphocytes to transfer antigen and initiate class switching in a primary T-dependent response . J Immunol , 161 ( 3 ): 1313 - 1319 . Dendritic cells interact directly with naive B lymphocytes to transfer antigen and initiate class switching in a primary T-dependent response Yang SC , Batra RK , Hillinger S , et al. , 2006 . Intrapulmonary administration of CCL21 gene-modified dendritic cells reduces tumor burden in spontaneous murine bronchoalveolar cell carcinoma . Cancer Res , 66 ( 6 ): 3205 - 3213 . https://doi.org/10.1158/0008-5472.CAN-05-3619 https://doi.org/10.1158/0008-5472.CAN-05-3619 Intrapulmonary administration of CCL21 gene-modified dendritic cells reduces tumor burden in spontaneous murine bronchoalveolar cell carcinoma Yeh CH , Finney J , Okada T , et al. , 2022 . Primary germinal center-resident T follicular helper cells are a physiologic ally distinct subset of CXCR5hiPD-1hi T follicular helper cells. Immunity , 55 ( 2 ): 272 - 289.e7 . https://doi.org/10.1016/j.immuni.2021.12.015 https://doi.org/10.1016/j.immuni.2021.12.015 Primary germinal center-resident T follicular helper cells are a physiologic Yoshida H , Naito A , Inoue J , et al. , 2002 . Different cytokines induce surface lymphotoxin-αβ on IL-7 receptor-α cells that differentially engender lymph nodes and Peyer’s patches . Immunity , 17 ( 6 ): 823 - 833 . https://doi.org/10.1016/s1074-7613(02)00479-x https://doi.org/10.1016/s1074-7613(02)00479-x Different cytokines induce surface lymphotoxin-αβ on IL-7 receptor-α cells that differentially engender lymph nodes and Peyer’s patches Jing CHEN was responsible for reference searching and manuscript writing, and Lie WANG and Jian CHEN for supervision and manuscript revision. All authors have approved the final manuscript. This work was supported by the Zhejiang Provincial Key Project of Research and Development (No. 2019C03043), the National Natural Science Foundation of China (Nos. 32030035, 31870874, 32000623, and 32100693), and the Zhejiang Provincial Natural Science Foundation (No. LZ21C080001) of China. 10.1631/jzus.B2200174 1673-1581（2022）10-0812-11 This work was supported by the Zhejiang Provincial Key Project of Research and Development (No. 2019C03043), the National Natural Science Foundation of China (Nos. 32030035, 31870874, 32000623, and 32100693), and the Zhejiang Provincial Natural Science Foundation (No. LZ21C080001) of China. 2022-03-28 2022-07-15 2022-10-15 2022-12-27 2022-08-25 Copyright © Zhejiang University and Springer-Verlag GmbH Germany, part of Springer Nature 2022 2022 浙江大学出版社 Jing CHEN, Jian CHEN, and Lie WANG declare that they have no conflict of interest. This review does not contain any studies with human or animal subjects performed by any of the authors. Compliance with ethics guidelines 浙江大学学报（英文版）（B辑：生物医学和生物技术） 10 23