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Abstract：
Functional roles of SIGLEC15 in hepatocellular carcinoma (HCC) were not clear, which was recently found to be an immune inhibitor with similar structure of inhibitory B7 family members. SIGLEC15 expression in HCC was explored in public databases and further examined by PCR analysis. SIGLEC15 and PD-L1 expression patterns were examined in HCC samples through immunohistochemistry. SIGLEC15 expression was knocked-down or over-expressed in HCC cell lines, and CCK8 tests were used to examine cell proliferative ability in vitro. Influences of SIGLEC15 expression on tumor growth were examined in immune deficient and immunocompetent mice respectively. Co-culture system of HCC cell lines and Jurkat cells, flow cytometry analysis of tumor infiltrated immune cells and further sequencing analyses were performed to investigate how SIGLEC15 could affect T cells in vitro and in vivo. We found SIGLEC15 was increased in HCC tumor tissues and was negatively correlated with PD-L1 in HCC samples. In vitro and in vivo models demonstrated inhibition of SIGLEC15 did not directly influence tumor proliferation. However, SIGLEC15 could promoted HCC immune evasion in immune competent mouse models. Knock-out of Siglec15 could inhibit tumor growth and reinvigorate CD8+ T cell cytotoxicity. Anti-SIGLEC15 treatment could effectively inhibit tumor growth in mouse models with or without mononuclear phagocyte deletion. Bulk and single-cell RNA sequencing data of treated mouse tumors demonstrated SIGLEC15 could interfere CD8+ T cell viability and induce cell apoptosis. In all, SIGLEC15 was negatively correlated with PD-L1 in HCC and mainly promote HCC immune evasion through inhibition of CD8+ T cell viability and cytotoxicity.
摘要：
SIGLEC15在肝细胞癌（HCC）中的功能作用尚不清楚，它是一种与抑制性B7家族成员结构相似的免疫抑制剂。在公共数据库中探索HCC中的SIGLEC15表达，并通过PCR分析进一步检查。通过免疫组织化学检查HCC样品中的SIGLEC15和PD-L1表达模式。SIGLEC15表达在HCC细胞系中被敲低或过表达，和CCK8试验用于检测体外细胞增殖能力。分别在免疫缺陷和免疫活性小鼠中检查了SIGLEC15表达对肿瘤生长的影响。肝癌细胞系与Jurkat细胞共培养系统,我们对肿瘤浸润的免疫细胞进行了流式细胞术分析,并进行了进一步的测序分析,以研究SIGLEC15在体外和体内如何影响T细胞.我们发现SIGLEC15在HCC肿瘤组织中升高，并且与HCC样本中的PD-L1呈负相关。体外和体内模型证明SIGLEC15的抑制不直接影响肿瘤增殖。然而,SIGLEC15可以促进免疫活性小鼠模型中的HCC免疫逃避。敲除Siglec15可以抑制肿瘤生长并恢复CD8T细胞的细胞毒性。在有或没有单核吞噬细胞缺失的小鼠模型中，抗SIGLEC15治疗可以有效抑制肿瘤生长。处理的小鼠肿瘤的大量和单细胞RNA测序数据表明SIGLEC15可以干扰CD8+T细胞活力并诱导细胞凋亡。总之,SIGLEC15在HCC中与PD-L1呈负相关，主要通过抑制CD8+T细胞活力和细胞毒性促进HCC免疫逃避。
