Lymphatic vasculature in tumor metastasis and immunobiology

Lymphatic vasculature in tumor metastasis and immunobiology 淋巴血管在肿瘤转移和免疫生物学中的作用 first-author †E-mail:xinguoj@stanford.edu †E-mail:xinguoj@stanford.edu xinguoj@stanford.edu VA Palo Alto Health Care System, Stanford University School of Medicine, Palo Alto, CA 94304, USA VA Palo Alto Health Care System, Stanford University School of Medicine, Palo Alto, CA 94304, USA Lymphatic vessels are essential for tissue fluid homeostasis, immune cell trafficking, and intestinal lipid absorption. The lymphatics have long been recognized to serve as conduits for distant tumor dissemination. However, recent findings suggest that the regional lymphatic vasculature also shapes the immune microenvironment of the tumor mass and potentiates immunotherapy. This review discusses the role of lymphatic vessels in tumor metastasis and tumor immunity. 淋巴系统被认为是肿瘤转移的重要途径之一,所以通常情况下肿瘤引起的淋巴血管增生会降低肿瘤预后,治疗上也建议淋巴清扫.但是最新的研究显示,淋巴系统可能对肿瘤免疫治疗有促进作用.这篇综述的主要目的是对相关领域做一个简短总结,以期待将来有更多的研究来关注淋巴系统对肿瘤治疗的影响.文章首先介绍肿瘤淋巴血管增生和淋巴转移的分子机制,然后介绍淋巴系统在肿瘤免疫中的作用,最后利用最新研究来证明淋巴系统有增强肿瘤免疫治疗的作用. Lymphatic Lymphatic endothelial cell (LEC) Cancer Metastasis Immunotherapy 淋巴系统 淋巴内皮细胞 肿瘤 转移 免疫治疗 Introduction 1 Metastasis is the primary cause of morbidity and mortality in cancer patients (Guan, 2015 2015 ). Although it was recognized centuries ago that patients with a higher tumor burden in sentinel lymph nodes have worse prognoses (Shayan et al., 2006 2006 ), the notion that the lymphatic vasculature is fundamental to tumor metastasis was appreciated only about two decades ago (Karaman and Detmar, 2014 2014 ). Pioneering murine studies demonstrated that the induction of lymphatic vascular overgrowth promotes tumor metastasis (Skobe et al., 2001 2001 ; Stacker et al., 2001 2001 ). A later clinical investigation revealed that tumor lymphatic vessel amplification predisposes human melanoma to metastasis (Dadras et al., 2003 2003 ). However, a recent study demonstrated that enhancing lymphangiogenesis augments the efficacy of cancer vaccine-and checkpoint blockade-mediated immunotherapy (Fankhauser et al., 2017 2017 ), providing the first evidence that the promotion of cancer lymphangiogenesis might be harnessed to potentiate immune modulatory treatments. Further investigation is, therefore, urgently needed to gain a better understanding of how lymphatics may affect tumor pathology. This review summarizes the role of the lymphatic vasculature in tumor metastasis as well as tumor immunobiology. Lymphatic vascular system 1 The lymphatic system is a unidirectional circulatory network that is essential for tissue fluid homeostasis, dietary fat absorption, and the regulation of immune responses (Jiang et al., 2018 2018 ). The lymphatic vascular tree begins as blind-ended capillaries comprised of a single layer of lymphatic endothelial cells (LECs) that tether to the surrounding tissue through anchoring filaments (Stacker et al., 2014 2014 ); junctional proteins, such as vascular endothelial cadherin (VE-cadherin), claudin-5, occludin, zonula occludens-1 (ZO-1), and endothelial cell-selective adhesion molecule (ESAM), form discontinuous button-like structures that interconnect capillary LECs and facilitate the uptake of interstitial fluid, macromolecules, and cells (Baluk et al., 2007 2007 ; Mortimer and Rockson, 2014 2014 ). The capillaries converge into pre-collectors that further merge into collecting lymphatics, where continuous zipper-like junctions join LECs (Baluk et al., 2007 2007 ). Collecting lymphatics are invested with smooth muscle cells and contain intraluminal valves that permit unidirectional lymph flow (Mäkinen et al., 2007 2007 ). Lymphatic vascular deficiency or dysfunction causes lymphedema, a chronic disfiguring disorder that affects millions of patients globally (Tian et al., 2017 2017 ; Jiang et al., 2018 2018 ; Rockson et al., 2018 2018 ). Also notable is the fact that pathological lymphatic remodeling occurs in a myriad of acute or chronic disorders, such as cardiac, pulmonary, renal, and neurodegenerative diseases, and improving the lymphatic circulation in those conditions appears to be beneficial (Aspelund et al., 2016 2016 ; Henri et al., 2016 2016 ; Stump et al., 2017 2017 ; da Mesquita et al., 2018 2018 ; Lopez Gelston et al., 2018 2018 ; Vieira et al., 2018 2018 ). This review focuses on lymphatics in cancer pathology. Tumor lymphangiogenesis 1 Lymphangiogenesis is the process of new lymphatic vessel formation from preexisting vasculature, a phenomenon that is important for both embryonic development and adult tissue homeostasis (Tammela and Alitalo, 2010 2010 ). It is a tightly regulated process that requires the coordination of multiple inter-and intracellular signaling cascades (Zheng et al., 2014 2014 ). The vascular endothelial growth factor (VEGF)-C/D-induced activity of VEGF receptor (VEGFR)-3 elicits the central signaling that stimulates lymphangiogenesis in both physiological and pathophysiological conditions (Jeltsch et al., 1997 1997 ). Other molecules, including fibroblast growth factor-2 (FGF2), angiopoietins, sphingosine-1-phosphate (S1P), neuropilin 2 (NRP2), bone morphogenetic protein 9 (BMP9), and Notch1, also participate in the generation of new lymphatic vasculature (Zheng et al., 2014 2014 ). Pro-lymphangiogenic interleukin (IL)-1β and tumor necrosis factor (TNF)-α and anti-lymphangiogenic IL-4 and IL-13 also regulate lymphangiogenesis, especially during inflammation (Baluk et al., 2009 2009 , 2013 2013 ; Shin et al., 2015 2015 ; Sainz-Jaspeado and Claesson-Welsh, 2018 2018 ). Furthermore, interstitial pressure and flow rate can guide lymphangiogenesis (Boardman and Swartz, 2003 2003 ). LEC-expressed proteases, such as matrix metalloproteinase (MMP) 9 and MMP2, and integrins, such as Itga9 and α5β1, are also involved in new lymphatic vasculature formation (Vaahtomeri et al., 2017 2017 ), suggesting that lymphangiogenesis requires extracellular matrix (ECM) remodeling as well as a bidirectional LEC and ECM communication. Analogous to that of blood vascular angiogenesis, the lymphangiogenic process utilizes the Notch signaling pathway to enhance lymphatic stabilization by promoting a stalk cell phenotype of proliferating LECs (Zheng et al., 2011 2011 ). More recently, LEC metabolic processes, such as fatty acid oxidation (FAO) and glycolysis, have been shown to regulate lymphangiogenesis (Wong et al., 2017 2017 ; Yu et al., 2017 2017 ), highlighting the importance of cellular metabolism in regulating lymphatic development and regeneration. Similar to that in tumor angiogenesis, tumor lymphangiogenesis produces abnormal lymphatic vessels, which allow retrograde fluid flow and make liquid transportation inefficient (Ariffin et al., 2014 2014 ). It was hypothesized that, during tumor progression, accumulating mutations enable tumor cells to produce pro-lymphangiogenic growth factors that initiate lymphangiogenesis, a process known as the lymphangiogenic switch (Cao, 2005 2005 ). For example, the mutation of the tumor suppressor gene p53 and the activation of oncogenes Ras and Myc enhance the expression of FGF2, VEGF, and platelet-derived growth factor (PDGF), which drives initial tumor lymphangiogenesis (Ueba et al., 1994 1994 ; Arbiser et al., 1997 1997 ; Enholm et al., 1997 1997 ; Su et al., 2001 2001 ; Uramoto et al., 2004 2004 ). Tumor cells can produce S1P and prostaglandin E2 (PGE2) to promote lymphatic growth (Nandi et al., 2017 2017 ; Yamada et al., 2018 2018 ). Tumors also indirectly enhance lymphatic growth by activating fibroblasts to secrete VEGF-C and hepatocyte growth factor (HGF) (Wei et al., 2017 2017 ; Gao et al., 2018 2018 ), as well as by recruiting tumor-associated macrophages (TAMs) and mast cells to produce VEGF-C/D and IL-1β (Harvey and Gordon, 2012 2012 ; Weichand et al., 2017 2017 ; Varricchi et al., 2018 2018 ). Moreover, escalated interstitial pressure, resulting primarily from increased blood vessel leakage, provides guidance cues and promotes lymphatic expansion (Kim et al., 2016 2016 ). A more recent study showed that the chemotherapeutic agent docetaxel reprograms breast cancer cells to preferentially express pro-lymphangiogenic factors, including VEGF-C and TNF-α to promote lymphatic sprouting (Harris et al., 2018 2018 ). Cumulatively, these findings suggest that cancer cells, tumor microenvironment, and treatment interventions enhance lymphangiogenesis and abnormal lymphatic remodeling in the tumor (Fig. 1 1 ). Tumor cells produce FGF2, PDGF, VEGF, S1P, and PGE2, which directly induce lymphangiogenesis. Tumor cells also activate fibroblasts and recruit inflammatory cells, including mast cells and macrophages, which in turn produce VEGF-C/D, HGF, and IL-1β to enhance lymphangiogenesis. Chemotherapy promotes lymphangiogenesis by reprogramming cancer cells to express VEGF-C and TNF-α. Interstitial fluid flow provides directional guidance for lymphangiogenesis. FGF2, fibroblast growth factor-2; PDGF, platelet-derived growth factor; VEGF, vascular endothelial growth factor; S1P, sphingosine-1-phosphate; PGE2, prostaglandin E2; HGF, hepatocyte growth factor; IL, interleukin; TNF, tumor necrosis factor Tumor-induced lymphangiogenesis also occurs in the draining lymph nodes, where new lymphatic vessel formation is observed to take place before the arrival of the metastatic tumor cells, indicating that circulating pro-lymphangiogenic factors that originate from the primary tumor mass may play a central role in this process (Hirakawa et al., 2005 2005 ). After arrival to the lymph nodes, tumor cells promote local lymphatic growth by continuously supplying VEGF-C (Kerjaschki et al., 2011 2011 ). Lymphatic vessel expansion in draining lymph nodes appears to be an important step for distant tumor metastasis (Hirakawa et al., 2007 2007 ; Karaman and Detmar, 2014 2014 ). Lymphatic routes for tumor metastasis 1 Decades of research has provided a comprehensive understanding of the cellular and molecular mechanisms involved in tumor metastasis through the blood vascular circulation (Lambert et al., 2017 2017 ). Tumor cell dissemination through the bloodstream involves a sequential, multiple-step invasion-metastasis cascade. During this process, tumor cells endure hydrodynamic flow and shear stress, as well as manage to escape destruction by circulating immune cells present in the blood circulation; tumor cells also develop programs that subvert the induced dormancy during transit, which allow cancer stem cells (CSCs) within the migrating cell population to maintain their ability to re-initiate tumor growth at distant new locations (Lambert et al., 2017 2017 ). Lymphatic metastasis, on the other hand, involves tumor cell transport in both lymphatic and blood vessels (Proulx and Detmar, 2013 2013 ; Paduch, 2016 2016 ). Mechanisms of immune cell trafficking in lymphatics are well-studied (Randolph et al., 2016 2016 ). Tumor cells highjack immune trafficking machinery to facilitate their own entry and transport within the lymphatic system. LEC-produced chemokines, including C-C motif chemokine ligand 21 (CCL21) and CCL19, are the most important factors that guide and recruit immune cells that express C-C motif chemokine receptor 7 (CCR7); mice lacking CCR7 expression have defective T cells and dendritic cells (DCs) homing to the lymph nodes (Förster et al., 2008 2008 ). Increased CCR7 expression occurs in several human cancers, and a higher level of CCR7 expression correlates with increased distant metastasis (Müller et al., 2001 2001 ), suggesting that tumor cell lymphatic invasion similarly employs CCR7-mediated chemotaxis. The CXCL12/CXCR4 and CX3CL1/CX3CR1 axes have been shown to play roles in directing DC trafficking (Imai et al., 1997 1997 ; Kabashima et al., 2007a 2007a , 2007b 2007b ; Jackson, 2014 2014 ). In tumors, chemokine receptor pairs, including CXCL12/CXCR4 and CCL1/CCR8, also play a role in promoting metastasis (Hirakawa et al., 2009 2009 ; Das et al., 2013 2013 ) (Fig. 2 2 ). Although tumor masses often display lymph stasis, this may not significantly impede cancer cell lymphatic intravasation, because cellular uptake depends primarily on the chemotactic guidance gradient (Randolph et al., 2016 2016 ). As for the site of entry, the immune cells prefer to use the regions of the lymphatic capillaries with sparse basement membrane, known as portals (Pflicke and Sixt, 2009 2009 ). Tumor cells likely also enter lymphatics primarily through those locations. While the bloodstream may pose multiple obstacles to circulating tumor cells (Lambert et al., 2017 2017 ), the lymphatic vasculature might provide a protective microenvironment that promotes the survival of in-transit tumor cells; LECs might also provide a niche for cells with CSC properties (Karaman and Detmar, 2014 2014 ). In summary, the lymphatic route likely has an advantage over the blood route for cancer cell dissemination, and the former may represent a preferable path for distant tumor dissemination (Mortimer and Rockson, 2014 2014 ). Tumor lymphatic vasculature not only primes the anti-tumor immunity but also induces suppressive immunity by producing molecules, including TGF-β, IDO, and NO. LEC expression of MHCs and PD-L1 confers them the ability to induce T cell tolerance by acting as tolerogenic APCs directly. Lymphatic vasculature provides a conduit for tumor metastasis; LEC expression of CCL21, CCL19, CXCL12, and CCL1 facilitates tumor cell lymphatic intravasation. Lymphatic-induced suppressive microenvironment not only negatively impacts anti-tumor immunity but also promotes metastasis. Promoting tumor lymphangiogenesis may augment the efficacy of immunotherapy. TGF, transforming growth factor; IDO, indoleamine-2,3-dioxygenase; NO, nitric oxide; LEC, lymphatic endothelial cell; MHC, major histocompatibility complex; PD-L1, programmed death-ligand 1; APC, antigen-presenting cell; CCL, C-C motif chemokine ligand; CXCL, C-X-C motif chemokine ligand Epithelial-mesenchymal transition (EMT) is a well-described phenomenon that occurs during blood vessel metastasis (Lambert et al., 2017 2017 ). Intriguingly, recent findings suggest that the EMT program may also play a role in lymphatic invasion (Karlsson et al., 2017 2017 ), which may sound counterintuitive, since the unique button-like structure of the lymphatic capillary does not seem to require cellular transformation for lymphatic intravasation. However, given the notion that the transitional state between the epithelial and mesenchymal phenotypes might skew malignant cells to CSCs and facilitate tumor re-growth (Lambert et al., 2017 2017 ), the EMT program in lymphatic dissemination may well be an important step. Lymphatic vessels in tumor immunobiology 1 Cancer is a genetic disease initiated by oncogenic mutations. Once formed, tumors typically gain additional mutations or epigenetic modifications to sustain their growth. Genomic diversity provides an advantage for cancer cell survival, but also increases the likelihood that those malignant cells might be detected and killed by the host immune system (Jiang and Shapiro, 2014 2014 ; Schumacher and Schreiber, 2015 2015 ; Chen and Mellman, 2017 2017 ). Although the lymphatic vessels are known to promote immunity (Hos and Cursiefen, 2014 2014 ), a positive correlation between lymphatic density and immune response in human cancer was not revealed until recently (Lund et al., 2016 2016 ). In transgenic mice (K14-VEGFR3-Ig) that lack dermal lymphatic vessels, syngeneic B16F10 melanoma displayed significantly lower infiltration of immune cells, including B cells, T cells, and proinflammatory myeloid cells, as well as diminished expression of a panel of inflammatory mediators (Lund et al., 2016 2016 ). This finding suggests that induction of tumor immunity requires functional lymphatic vasculature. Consistent with this observations, lymphatic vessels were shown to facilitate tumor antigen-loaded DC trafficking and T cell priming (Roberts et al., 2016 2016 ); in B16 melanoma-bearing mice with dysfunctional lymphatics, the draining lymph nodes have decreased levels of tumor antigens and lower numbers of cytotoxic CD8 + T cells, and those cells possess lower anti-tumor cytotoxicity (Kimura et al., 2015 2015 ). In agreement with these preclinical findings, a clinical study showed that, in colorectal cancers (CRCs), distant metastasis occurs more frequently when tumors have a lower immune cytotoxicity profile (Mlecnik et al., 2016 2016 ). The same study showed that tumors with lower peritumoral lymphatic vascular density tend to be more metastatic, indicating a positive correlation between lymphatic vascular density and tumor immune cytotoxicity profile. These investigations collectively demonstrate that the lymphatics participate in promoting anti-tumor immune responses and in shaping the tumor immune microenvironment. Development of anti-tumor immunity takes place primarily in tumor-draining lymph nodes (TDLNs) (Chandrasekaran and King, 2014 2014 ; Yeo and Angeli, 2017 2017 ). Newly formed tumor lymphatic vasculature provides a conduit for the transportation of tumor antigens to the draining lymph nodes to facilitate T cell priming (Thomas et al., 2016 2016 ). Through the lymph flow, tumor-derived antigens can be directly delivered to DCs or B cells residing in the TDLNs (Roozendaal et al., 2009 2009 ; Thomas et al., 2016 2016 ). DCs patrolling peripheral tissues also take up tumor antigens, enter lymphatic vessels, and invade TDLNs (Thomas et al., 2016 2016 ). Antigen-loaded DCs then prime naive T cells and induce antigen-specific anti-tumor immunity. It is worth noting that the local immune signaling microenvironment during antigen presentation may influence the quality of the adaptive immunity, i.e., immune activation or tolerance (Nishikawa and Sakaguchi, 2014 2014 ; Thomas et al., 2016 2016 ). The lymphatic vasculature within the tumor may also impact TDLN architecture and function by influencing the delivery of inflammatory modulators, exosomes, and microparticles from the tumor microenvironment (Robbins and Morelli, 2014 2014 ; Rohner et al., 2015 2015 ). In line with the role of TDLNs in promoting anti-tumor immunity, nanoparticle-mediated adjuvant therapy targeting TDLNs enhanced tumor immunity characterized by increased cytotoxic T cells and decreased Treg cells within TDLNs (Thomas et al., 2014 2014 ). Therapeutic vaccination targeting TDLNs also enhanced anti-tumor immunity (Jeanbart et al., 2014 2014 ). Elevation of CCL3 expression in the tumor microenvironment resulted in reduced tumor growth, presumably by enhancing DC homing to TDLNs and strengthening anti-tumor immunity (Allen et al., 2017 2017 ). Furthermore, effective checkpoint inhibition therapy requires functional TDLNs (Fransen et al., 2018 2018 ). These studies indicated that TDLNs are not only vital for the development of anti-tumor immunity but also critical for the acquisition of optimal immunotherapeutic efficacy. In addition to their function in immune activation, lymph nodes are important sites for the maintenance of self-tolerance (Förster et al., 2008 2008 ). The lymphatic vasculature also controls self-tolerance by providing a conduit for lymph-borne antigen transportation and regulating the structural organization of the draining lymph nodes (Thomas et al., 2016 2016 ). The lymphatic system not only elicits anti-tumor immune responses but also promotes tolerance against tumors (Chen and Mellman, 2017 2017 ). Recent studies provided evidence that LECs participate in the induction of peripheral tolerance through diverse mechanisms, under both physiological and pathological conditions (Card et al., 2014 2014 ; Randolph et al., 2016 2016 ; Cui et al., 2017 2017 ). Because LECs express peripheral tissue antigens and major histocompatibility complex (MHC) molecules, they can directly recognize and suppress T cell activation when the expression levels of inhibitory receptor programmed death-ligand 1 (PD-L1) are high and those of co-stimulatory molecules are low (Lee et al., 2007 2007 ; Nichols et al., 2007 2007 ; Malhotra et al., 2012 2012 ; Tewalt et al., 2012 2012 ). LEC expression of PD-L1 was later shown to be strongly induced by interferon γ (IFNγ) (Dieterich et al., 2017 2017 ), and lymphatic-specific deletion of IFNγ receptor (IFNγR) dampened LEC-mediated immune suppression and enhanced tumor immunity (Lane et al., 2018 2018 ). Because IFNγ is a cytokine that marks immune activation and is produced predominantly by immune effector cells (Schoenborn and Wilson, 2007 2007 ), PD-L1 induction by IFNγ may represent a natural feedback mechanism employed by the immune system to achieve equilibrium. LECs also produce immunosuppressive mediators, including transforming growth factor-β (TGF-β), nitric oxide (NO), and indoleamine-2,3-dioxygenase (IDO), to induce tolerant DCs and suppress T cell function (Lukacs-Kornek et al., 2011 2011 ; Nörder et al., 2012 2012 ; Christiansen et al., 2016 2016 ). Accordingly, the lymphatics not only induce an active immune response characterized by CD8 + T cell infiltration but also foster a suppressive microenvironment by increasing LEC expression of IDO, inducible nitric oxide synthase (iNOS), and arginase-1 in human tumors (Bordry et al., 2018 2018 ). Lastly, the lymphatic system can also induce tolerance by directly presenting tumor-derived antigens to activated CD8 + T cells to suppress their activity (Lund et al., 2012 2012 ). Collectively, these recent findings indicated that tumor lymphatics control both immune activation and tolerance (Fig. 2 2 ). Concluding remarks 1 The lymphatic circulatory system is relatively understudied in cancer compared to the blood vascular system (Folkman, 1971 1971 ). Recent advances indicate that the tumor-associated lymphatic vasculature is not just a passive conduit for metastasis; it also fulfills vital functions in shaping the immune and inflammatory responses of the tumor microenvironment. 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Compliance with ethics guidelines Xinguo JIANG declares that he has no conflict of interest. This article does not contain any studies with human or animal subjects performed by the author. 10.1631/jzus.B1800633 Project supported by the National Institutes of Health (NIH), USA (No. K12 HL120001-05) 2018-12-19 2019-04-12 2022-01-05 Copyright © Zhejiang University and Springer-Verlag GmbH Germany, part of Springer Nature 2020 2020 Journal of Zhejiang University-SCIENCE B (Biomedicine and Biotechnology) 01 21