High levels of serum IL-10 indicate disease progression, extramedullary involvement, and poor prognosis in multiple myeloma

High levels of serum IL-10 indicate disease progression, extramedullary involvement, and poor prognosis in multiple myeloma 血清高水平白细胞介素-10提示多发性骨髓瘤患者疾病进展、髓外累及和不良预后 1 first-author 1 1 1 1 1 1 1 1 1 2 3 4 1 corresp Jingsong HE, hejingsong@zju.edu.cn Jingsong HE, hejingsong@zju.edu.cn hejingsong@zju.edu.cn https://orcid.org/0000-0002-1190-1037 Bone Marrow Transplantation Center, Department of Hematology, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China Bone Marrow Transplantation Center, Department of Hematology, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China 浙江大学医学院附属第一医院血液科＆骨髓移植中心，中国杭州，310003 浙江大学医学院附属第一医院血液科＆骨髓移植中心，中国杭州，310003 Institute of Hematology, Zhejiang University, Hangzhou 310058, China Institute of Hematology, Zhejiang University, Hangzhou 310058, China 浙江大学血液学研究所，中国杭州，310058 浙江大学血液学研究所，中国杭州，310058 Zhejiang Laboratory for Systems & Precision Medicine, Zhejiang University Medical Center, Hangzhou 311121, China Zhejiang Laboratory for Systems & Precision Medicine, Zhejiang University Medical Center, Hangzhou 311121, China 浙江大学医学中心，浙江省系统&精准医学实验室，中国杭州，311121 浙江大学医学中心，浙江省系统&精准医学实验室，中国杭州，311121 Institute of Hematology, Department of Hematology, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China Institute of Hematology, Department of Hematology, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China 浙江大学医学院附属第一医院血液科&血液学研究所，中国杭州，310003 浙江大学医学院附属第一医院血液科&血液学研究所，中国杭州，310003 多发性骨髓瘤（MM）细胞的生长和存活依赖于骨髓微环境，其中细胞因子常与疾病的不良预后有关。在新药治疗时代，血清细胞因子水平对MM预后作用需进一步评估。本研究分析了157例初诊MM患者外周血细胞因子水平（包括白细胞介素-2（IL-2）、IL-4、IL-6、IL-10、干扰素γ（IFN-γ）、肿瘤坏死因子α（TNF-α）和IL-17A）与患者基线临床特征、疗效以及预后之间的关系。并选用15例年龄契合的健康志愿者和96例复发MM患者作为对照。所有患者均一线接受硼替佐米为基础方案的治疗。生存分析表明，上述细胞因子中，仅血清IL-10与患者的无进展生存期（PFS）和总生存期（OS）显著相关。初诊MM患者中，有103例（65.6%）患者被归为高IL-10（≥1.42 pg/mL）组，该组患者通常具有高危基因异常和临床分期，也更容易出现贫血、血小板减少，以及血清乳酸脱氢酶、C-反应蛋白和肌酐水平增高的症状。单因素分析表明高IL-10组患者有更差的PFS（ P ＝0.040）和OS（ P < 0.001），多因素分析提示血清IL-10是初诊MM患者OS的独立预后因素。研究结果提示，血清IL-10水平与MM患者疾病进展和高危临床特征相关，可作为以硼替佐米为基础治疗方案的初诊MM患者OS的预后因素。 多发性骨髓瘤 白细胞介素-10 临床特征 无进展生存期 总生存期 Multiple myeloma (MM) is a common malignant hematological tumor in adults, which is characterized by clonal malignant proliferation of plasma cells in the bone marrow and secretion of a large number of abnormal monoclonal immunoglobulins (M protein), leading to bone destruction, hypercalcemia, anemia, and renal insufficiency ( Alexandrakis et al., 2015 Alexandrakis et al., 2015 ; Yang et al., 2018 Yang et al., 2018 ). Since a large number of new drugs, represented by proteasome inhibitors and immunomodulators, have been successfully used to treat MM, treatment efficacy and survival of patients have been significantly improved. However, due to the high heterogeneity of this disease, patients have responded differently to treatments with these new drugs ( Palumbo and Anderson, 2011 Palumbo and Anderson, 2011 ; Wang et al., 2016 Wang et al., 2016 ; Huang et al., 2020 Huang et al., 2020 ). Growth and survival of MM cells depend on the bone marrow microenvironment, especially numerous inflammatory cytokines secreted by myeloma cells and bone marrow stromal cells, such as vascular endothelial growth factor (VEGF), interleukin (IL)‍-6, transforming growth factor-‍β (TGF‍‍-‍‍β), and IL-10. These cytokines can promote the growth of myeloma cells, induce angiogenesis, and inhibit antitumor immunity, and are often linked to patient prognosis ( Kumar et al., 2017 Kumar et al., 2017 ). In this era of new drugs, the prognostic values of the serum levels of these cytokines in MM need further evaluation. Therefore, in this study we retrospectively ana‍lyzed the prognostic values of peripheral blood inflammatory factor levels for newly diagnosed MM (NDMM) patients treated with bortezomib as first-line therapy. A total of 157 NDMM patients chosen according to 2014 International Myeloma Working Group (IMWG) diagnostic criteria ( Rajkumar et al., 2014 Rajkumar et al., 2014 ) were enrolled. They were first seen and treated in the First Affiliated Hospital, School of Medicine, Zhejiang University (Hangzhou) between November 2014 and September 2018. Patients received a bortezomib-based regimen as the first-line induction treatment ( He et al., 2020 He et al., 2020 ). Young and physically fit patients with partial remission or better efficacy voluntarily chose to receive autologous stem cell transplantation (ASCT). Then patients were treated with dexamethasone combined with bortezomib or lenalidomide for 2‍‒‍3 years or until the disease progressed. The clinical characteristics of the NDMM patients at baseline are shown in Table 1 Table 1 . Data are presented as median (range) or number (percentage). NDMM: newly diagnosed multiple myeloma; D-S: Durie-Salmon staging; ISS: international staging system; R-ISS: revised ISS; CRP: C-reactive protein; LDH: lactate dehydrogenase; Cr: creatinine; IL-2: interleukin-2; TNF-‍α: tumor necrosis factor-‍α; IFN-‍γ: interferon-‍γ; BMPC: bone marrow plasma cell; PD: bortezomib, dexamethasone; PAD: bortezomib, dexamethasone, adriamycin; PCD: bortezomib, dexamethasone, cyclophosphamide; PTD: bortezomib, dexamethasone thalidomide; ASCT: autologous stem cell transplantation. Baseline characteristics Data Total 157 Age (years) 64 (44‒80) Male 89 (56.7%) D-S 1+2+3A 131 (83.4%) 3B 26 (16.6%) ISS 1+2 99 (63.1%) 3 58 (36.9%) R-ISS ( n =147) 1+2 108 (73.5%) 3 39 (26.5%) CRP (mg/L) 2.0 (0‒204.2) LDH (U/L) 180 (79‒5785) Cr (μmol/L) 88 (39‒1033) IL-2 (pg/mL) 0.10 (0.10‒11.74) IL-4 (pg/mL) 0.10 (0.10‒6.01) IL-6 (pg/mL) 4.32 (0.10‒1657.79) IL-10 (pg/mL) 0.48 (0.10‒49.26) TNF-‍α (pg/mL) 0.10 (0.10‒108.90) IFN-γ (pg/mL) 0.10 (0.10‒17.61) IL-17A (pg/mL) 0.10 (0.10‒21.02) Genetic abnormalities ( n =142) Standard risk 62 (43.7%) High risk 80 (56.3%) BMPC percentage (%) 27.0 (0‒97.0) Therapy received PD 32 (20.4%) PAD 22 (14.0%) PCD 91 (58.0%) PTD 5 (3.2%) ASCT 20 (12.7%) All of the NDMM patients were tested for peripheral blood cytokine levels, including IL-2, IL-4, IL-6, IL-10, tumor necrosis factor-‍α (TNF-‍‍α), interferon-‍γ (IFN-‍γ), and IL-17A, before the first dose of anti-myeloma treatment. We quantified serum concentrations of the seven aforementioned cytokines using the BD TM Cytometric Bead Array (CBA) Human Th1/Th2/Th17 Cytokine Kit (BD Biosciences, San Jose, CA, USA). The optimal cutoff value of cytokines was based on the receiver operating characteristic (ROC) curve. According to the ROC curve, the best cutoff value for serum IL-10 was 1.42 pg/mL, with an area under the curve (AUC) value of 0.726, and the sensitivity and specificity were 65.3% and 79.6%, respectively ( Fig. 1 Fig. 1 ). Overall, 103 patients (65.6%) were classified into the low IL-10 group, and 54 (34.4%) patients were classified into the high IL-10 group. The optimal cutoff values of all indicators are presented in Tables 2 2 and 3 3 . PFS: progression-free survival; NDMM: newly diagnosed multiple myeloma; HR: hazard ratio; CI: confidence interval; D-S: Durie-Salmon staging; ISS: international staging system; R-ISS: revised ISS; CRP: C-reactive protein; LDH: lactate dehydrogenase; Cr: creatinine; IL-2: interleukin-2; TNF-‍‍α: tumor necrosis factor-‍α; IFN-‍γ: interferon-γ; BMPC: bone marrow plasma cell; PR: partial remission. 2 Variable 2 Univariable analysis 2 Multivariable analysis HR (95% CI) P value HR (95% CI) P value Age (>55 years) 0.96 (0.58‒1.60) 0.877 D-S (3B vs. 1+2+3A) 1.74 (1.02‒2.94) 0.044 2.01 (1.09‒3.68) 0.024 ISS (3 vs. 1+2) 1.98 (1.13‒3.47) 0.542 R-ISS (3 vs. 1+2) 1.54 (0.95‒2.49) 0.077 CRP (≥1.18 mg/L) 1.11 (0.71‒1.73) 0.663 LDH (≥250 U/L) 2.49 (1.47‒4.20) 0.001 Cr (≥177 μmol/L) 1.61 (0.93‒2.78) 0.090 IL-2 (≥0.22 pg/mL) 1.28 (0.80‒2.04) 0.310 IL-4 (≥0.75 pg/mL) 0.89 (0.38‒2.07) 0.778 IL-6 (≥0.49 pg/mL) 0.90 (0.50‒1.59) 0.706 IL-10 (≥1.42 pg/mL) 1.58 (1.02‒2.46) 0.040 TNF-α (≥0.17 pg/mL) 0.92 (0.59‒1.44) 0.726 IFN-γ (≥0.52 pg/mL) 1.03 (0.60‒1.80) 0.908 IL-17A (≥2.51 pg/mL) 1.17 (0.66‒2.09) 0.592 BMPC percentage (≥30%) 1.97 (1.27‒3.07) 0.002 1.90 (1.20‒3.01) 0.007 Genetic abnormalities (high risk) 2.16 (1.34‒3.50) 0.001 Extramedullary lesions (Yes) 5.32 (1.92‒14.77) <0.001 5.69 (1.36‒23.75) 0.017 Treatment response (<PR) 6.42 (3.04‒13.52) <0.001 4.95 (1.59‒15.43) 0.006 OS: overall survival; NDMM: newly diagnosed multiple myeloma; HR: hazard ratio; CI: confidence interval; D-S: Durie-Salmon staging; ISS: international staging system; R-ISS: revised ISS; CRP: C-reactive protein; LDH: lactate dehydrogenase; Cr: creatinine; IL-2: interleukin-2; TNF-α: tumor necrosis factor-‍α; IFN-γ: interferon-γ; BMPC: bone marrow plasma cell; PR: partial remission. 2 Variable 2 Univariable analysis 2 Multivariable analysis HR (95% CI) P value HR (95% CI) P value Age (>55 years) 2.65 (1.05‒6.71) 0.032 D-S (3B vs. 1+2+3A) 3.56 (1.94‒6.42) <0.001 ISS (3 vs. 1+2) 2.51 (1.42‒4.43) 0.002 R-ISS (3 vs. 1+2) 3.27 (1.79‒5.98) <0.001 2.87 (1.47‒5.62) 0.002 CRP (≥1.18 mg/L) 1.60 (0.85‒3.03) 0.145 LDH (≥250 U/L) 4.70 (2.60‒8.51) <0.001 Cr (≥177 μmol/L) 3.70 (2.03‒6.75) <0.001 IL-2 (≥0.22 pg/mL) 0.76 (0.34‒1.70) 0.505 IL-4 (≥0.75 pg/mL) 1.66 (0.67‒4.12) 0.278 IL-6 (≥0.49 pg/mL) 0.64 (0.32‒1.29) 0.642 IL-10 (≥1.42 pg/mL) 4.68 (2.59‒8.44) <0.001 4.32 (2.23‒8.39) <0.001 TNF-α (≥0.17 pg/mL) 1.10 (0.62‒1.97) 0.741 IFN-γ (≥0.52 pg/mL) 1.74 (0.93‒3.24) 0.078 IL-17A (≥2.51 pg/mL) 1.46 (0.73‒2.94) 0.286 BMPC percentage (≥30%) 2.26 (1.25‒4.10) 0.007 2.17 (1.14‒4.16) 0.019 Genetic abnormalities (high risk) 2.72 (1.36‒5.47) 0.003 Extramedullary lesions (Yes) 7.45 (2.54‒21.79) <0.001 Treatment response (<PR) 8.18 (3.75‒17.83) <0.001 10.82 (3.71‒31.52) <0.001 All NDMM patients were followed up until June 30, 2020. The median duration of follow-up was 30.5 months (95% confidence interval (CI): 1.1‍‍‒67.1 months), the median progression-free survival (PFS) time was 29.2 months (95% CI: 21.8‍‒36.5 months), and the median overall survival (OS) was not reached. We used Cox proportional hazards model to perform univariate and multivariate analyses (Tables 2 2 and 3 3 ). Univariate analysis showed that higher serum IL-10 level was tied to worse PFS and OS in NDMM patients, and serum IL-10 level was also an independent factor for poor OS in NDMM patients. This result was in line with the study by Shekarriz et al. (2018) Shekarriz et al. (2018) . However, other serum cytokine levels did not affect PFS or OS in NDMM patients treated with bortezomib. IL-10 is a major inflammatory inhibitor in the tumor microenvironment (TME), mainly secreted by monocytes/macrophages, T lymphocytes, B lymphocytes, natural killer (NK) cells, and mast cells ( Musolino et al., 2017 Musolino et al., 2017 ), and participates in the pathophysiological development of a variety of hematological malignancies, including chronic lymphocytic leukemia (CLL), non-Hodgkin’s lymphoma (NHL), and MM. It is negatively correlated with prognosis for the disease ( Fayad et al., 2001 Fayad et al., 2001 ; Načinović-Duletić et al., 2008 Načinović-Duletić et al., 2008 ; Gupta et al., 2012 Gupta et al., 2012 ; Shekarriz et al., 2018 Shekarriz et al., 2018 ). Then we analyzed the survival of patients with different serum IL-10 levels. Using the Kaplan-Meier method to generate survival curves, we compared the difference between the curves using the log-rank test. Patients in the high IL-10 group had worse PFS and OS than those in the low IL-10 group ( P =0.040 and P < 0.001, respectively). The median PFS was 17.7 months (95% CI: 13.7‍‒‍21.7 months) and 33.2 months (95% CI: 26.6‒‍39.8 months) for the high and low IL-10 groups, respectively ( Fig. 2 Fig. 2 a), and the median OS was 28.5 months (95% CI: 20.9‒‍36.0 months) and not reached, respectively ( Fig. 2 Fig. 2 b). However, the mechanism of IL-10 leading to poor survival in MM patients has not been fully elucidated. In diffuse large B cell lymphoma (DLBCL), it has been reported that IL-10 signaling can activate the Janus kinase (JAK) signaling pathway in lymphoma cells and promote expression of oncogenes, such as c-myc . The same study suggested that serum IL-10 might be a biomarker to identify patients that are more likely to respond to JAK inhibitors ( Gupta et al., 2012 Gupta et al., 2012 ). In addition to acting directly on tumor cells and TME, IL-10, as an important immunosuppressive cytokine, has the additional effect of blocking anti-tumor immunity ( Minnie et al., 2018 Minnie et al., 2018 ). Subsequently, we analyzed the relationship between serum IL-10 and clinical characteristics and therapy efficacy. The results indicated that high serum IL-10 was associated with high risk in there different staging systems: Durie-Salmon staging (D-S), international staging system (ISS), and revised ISS (R-ISS). In addition, patients with high serum IL-10 were more likely to have anemia or thrombocytopenia, elevated serum lactate dehydrogenase (LDH), C-reactive protein (CRP), or creatinine (Cr) level, and high-risk cytogenetic abnormalities (17p-, 1q+, and immunoglobulin heavy-chain (IgH) translocation) ( Table 4 Table 4 ). The treatment efficacy in 157 patients was evaluated after treatment. The overall response rates (ORRs) in the low and high IL-10 groups were 96.1% and 90.7% ( P =0.169), the complete remission (CR) rates were 45.6% and 40.7% ( P =0.558), and ≥very good partial remission rates (VGPRs) were 65.0% and 57.4% ( P =0.348), respectively. In the study by Wang et al. (2016) Wang et al. (2016) , 55.3% (104/188) of patients received the traditional chemotherapy regimen, and it was confirmed that serum IL-10 levels were negatively correlated with treatment efficacy. However, our study did not find a significant correlation between elevated IL-10 serum levels and treatment efficacy, possibly because all patients in our study were treated with a bortezomib-based regimen that overcame the adverse effects of serum IL-10 to a certain extent. P value of < 0.05 is in bold. IL-10: interleukin-10; D-S: Durie-Salmon staging; ISS: international staging system; R-ISS: revised ISS; Hb: hemoglobin; Plt: platelets; CRP: C-reactive protein; LDH: lactate dehydrogenase; Cr: cre`atinine; BMPC: bone marrow plasma cell; PR: partial remission. 2 Characteristics 2 IL-10 2 P value < 1.42 pg/mL ( n =103) ≥1.42 pg/mL ( n =54) Age (years) ≤55 37 (35.9%) 25 (46.3%) 0.207 >55 66 (64.1%) 29 (53.7%) Sex Male 59 (57.3%) 30 (55.6%) 0.836 Female 44 (42.7%) 24 (44.4%) D-S 1+2+3A 96 (93.2%) 35 (64.8%) <0.001 3B 7 (6.8%) 19 (35.2%) ISS 1 44 (42.7%) 9 (16.7%) 0.003 2 28 (27.2%) 18 (33.3%) 3 31 (30.1%) 27 (50.0%) R-ISS 1 16 (15.5%) 2 (3.7%) 0.008 2 63 (61.2%) 27 (50.0%) 3 18 (17.5%) 21 (38.9%) Hb (g/L) <80 21 (20.4%) 22 (40.7%) 0.007 ≥80 82 (79.6%) 32 (59.3%) Plt (×10 9 L -1 ) <150 32 (31.1%) 26 (48.1%) 0.035 ≥150 71 (68.9%) 28 (51.9%) LDH (U/L) <250 95 (92.2%) 35 (64.8%) <0.001 ≥250 8 (7.8%) 19 (35.2%) CRP (mg/L) <1.18 44 (42.7%) 13 (24.7%) 0.021 ≥1.18 59 (57.3%) 41 (75.9%) Cr (μmol/L) <177 97 (94.2%) 34 (63.0%) <0.001 ≥177 6 (5.8%) 20 (37.0%) BMPC percentage (%) <30 60 (58.3%) 31 (57.4%) 0.919 ≥30 43 (41.7%) 23 (42.6%) Genetic abnormalities Standard risk 46 (50.5%) 16 (31.4%) 0.027 High risk 45 (49.5%) 35 (68.6%) Extramedullary lesions No 101 (98.1%) 51 (94.4%) 0.340 Yes 2 (1.9%) 3 (5.6%) Treatment response ≥PR 99 (96.1%) 49 (90.7%) 0.169 <PR 4 (3.9%) 5 (9.3%) The serum IL-10 concentration in MM patients has been found to be significantly higher than that in healthy volunteers ( Shekarriz et al., 2018 Shekarriz et al., 2018 ). Therefore, we recruited 15 age-matched healthy volunteers and 96 refractory/relapsed MM (RRMM) patients treated in our hospital during the same period, so that we could test and compare the differences in serum IL-10 levels among healthy volunteers, NDMM, and RRMM patients. The 15 healthy volunteers included nine males and six females with a median age of 61 years (range, 48‍‒‍71 years), and there was no statistical difference in the gender or age between NDMM patients and healthy volunteers ( P =0.825 and P =0.509, respectively). The median prior regimen of 96 RRMM patients was 3 (range, 1‍‒‍5), including 60 males (62.5%) and 36 females (37.5%), and the median age was 60 years (range, 41‍‍‒‍80 years). There were no differences in baseline clinical characteristics between RRMM and NDMM patients. Our findings showed that the median concentration of serum IL-10 in healthy volunteers was 0.10 pg/mL (range, 0.10‍‒‍0.71 pg/mL), significantly lower than that in NDMM patients (0.48 pg/mL (range, 0.10‍‒‍49.26 pg/mL); P =0.002), while the median concentration of serum IL-10 in RRMM patients was 2.55 pg/mL (range, 0.10‍‒1916.74 pg/mL), significantly higher than that in NDMM patients ( P < 0.001; Fig. 3). Further prospective studies should be conducted in the initial and relapsed cases of the same group of MM patients to further confirm the correlation between serum IL-10 level and disease status. Most MM cells are confined to the bone marrow, and in some cases, malignant plasma cells can involve paraosseous tissue, known as extramedullary-bone related (EM-B), and even enter the blood circulation and colonize distant tissue to form extramedullary-extraosseous (EM-E) lesions. However, it is generally assumed that EM-B does not significantly affect patient survival, while patients with EM-E have very poor survival rates ( He et al., 2021 He et al., 2021 ). In a single-cell sequencing study involving a small sample, it was found that tumor cells in extramedullary MM lesions had higher expression of IL-10 and its receptor than those in intramedullary MM cells ( Ryu et al., 2020 Ryu et al., 2020 ); however, no studies have yet suggested a correlation between serum IL-10 level and EME. In this study, there were a total of 19 patients who had EME involvement of the 253 patients with NDMM and RRMM, 5 (3.2%) NDMM and 14 (14.6%) RRMM patients. The serum IL-10 levels of the 19 EME patients were significantly higher than those of patients without EME involvement, 5.90 pg/mL (range, 0.10‍‒‍1916.74 pg/mL) vs. 1.07 pg/mL (range, 0.10‒‍66.79 pg/mL) ( P < 0.001). In summary, our study confirmed that serum IL-10 levels are associated with disease progression and high-risk clinical characteristics, and significantly affect PFS and OS in NDMM patients. Additionally, the cox proportional hazards model demonstrated that serum IL-10 is an independent prognostic factor for OS among NDMM patients treated with bortezomib-based regimens. Therefore, as a simple, economical prognostic indicator, serum IL-10 could be applied in clinical work because it has significant prognostic value for MM patients. Nonetheless, this conclusion needs to be validated by prospective research using a larger number of cases. Materials and methods 1 Detailed methods are provided in the electronic supplementary materials of this paper. References Alexandrakis MG , Goulidaki N , Pappa CA , et al. , 2015 . Interleukin-10 induces both plasma cell proliferation and angiogenesis in multiple myeloma . 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Br J Cancer , 114 ( 4 ): 463 - 468 . https://doi.org/10.1038/bjc.2016.11 https://doi.org/10.1038/bjc.2016.11 High level of interleukin-10 in serum predicts poor prognosis in multiple myeloma Yang RN , Chang Q , Meng XC , et al. , 2018 . Prognostic value of systemic immune-inflammation index in cancer: a meta-analysis . J Cancer , 9 ( 18 ): 3295 - 3302 . https://doi.org/10.7150/jca.25691 https://doi.org/10.7150/jca.25691 Prognostic value of systemic immune-inflammation index in cancer: a meta-analysis Xiaoyan YUE wrote and translated part of the manuscript, reviewed literature, managed the patients, and collected clinical data. Linlin HUANG, Yang YANG, Yi ZHAO, Donghua HE, Xiaoyan HAN, Gaofeng ZHENG, Yi LI, Enfang ZHANG, Zhen CAI, and Xin HUANG reviewed and wrote a part of the manuscript and provided suggestions. Jingsong HE wrote a part of the manuscript, reviewed the literature, managed the patients, collected clinical data, and provided suggestions. All authors have read and approved the final manuscript, and therefore, have full access to all the data in the study and take responsibility for the integrity and security of the data. This work was supported by the National Natural Science Foundation of China (Nos. 81800201 and 81872322), the Zhejiang Key Research and Development Project (No. 2020C03014), and the Key Project of Zhejiang Provincial Natural Science Foundation of China (No. LZ22H160009). 10.1631/jzus.B2200277 1673-1581（2022）11-0968-07 This work was supported by the National Natural Science Foundation of China (Nos. 81800201 and 81872322), the Zhejiang Key Research and Development Project (No. 2020C03014), and the Key Project of Zhejiang Provincial Natural Science Foundation of China (No. LZ22H160009). 2022-05-30 2022-07-28 2022-11-15 2022-12-27 2022-10-16 Copyright © Zhejiang University and Springer-Verlag GmbH Germany, part of Springer Nature 2022 2022 浙江大学出版社 Xiaoyan YUE, Linlin HUANG, Yang YANG, Yi ZHAO, Donghua HE, Xiaoyan HAN, Gaofeng ZHENG,Yi LI, Enfan ZHANG, Zhen CAI, Xin HUANG, and Jingsong HE declare that they have no conflict of interest. The studies involving human participants were reviewed and approved by the Ethics Committee of the First Affiliated Hospital of Zhejiang University (No. IIT20210091A). All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2008 (5). Informed consent was obtained from all patients for being included in the study. Compliance with ethics guidelines Supplementary information 1 Materials and methods 浙江大学学报（英文版）（B辑：生物医学和生物技术） 11 23