B7-H3 confers resistance to Vγ9Vδ2 T cell-mediated cytotoxicity in human colon cancer cells via the STAT3/ULBP2 axis
B7-H3 confers resistance to Vγ9Vδ2 T cell-mediated cytotoxicity in human colon cancer cells via the STAT3/ULBP2 axis
复制标题
B7-H3 通过 STAT3/ULBP2 轴赋予人结肠癌细胞对 Vγ9Vγ2 T 细胞介导的细胞毒性的抵抗力
DOI：
10.1007/s00262-020-02771-w
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发表时间：
2020-10-29
影响因子：
5.8
通讯作者：
Chen, Weichang
中科院分区：
文献类型：
--
作者：
Lu, Huimin;Ma, Yanchao;Chen, Weichang
基于γ δ T细胞的免疫治疗在包括结肠癌（CC）在内的实体肿瘤中效率有限。肿瘤细胞的免疫逃避可能是基于γ δ T细胞治疗困难的主要原因。在本研究中，我们探讨了B7-H3是否以及如何调节CC细胞对V γ 9V δ 2 (V δ 2) T细胞毒性的抗性。我们在体外和体内观察到B7-H3的过表达促进了CC细胞对V δ 2 T细胞的杀伤作用，而B7-H3的敲低抑制了CC细胞对V δ 2 T细胞的杀伤作用。在机制上，我们发现b7 - h3介导的CC细胞对V δ 2 T细胞毒性的抗性涉及一个包括STAT3激活和ULBP2表达降低的分子途径。ULBP2阻断或敲低可消除B7-H3沉默诱导的V δ 2 T细胞对CC细胞的细胞毒性增加。此外，STAT3磷酸化抑制剂隐丹参酮（cryptotanshinone）逆转了B7-H3过表达诱导的ULBP2表达下降，并减弱了V δ 2 T细胞对CC细胞的杀伤作用。B7-H3与ULBP2在CC患者肿瘤组织中的表达呈负相关。我们的研究结果表明，b7 - h3介导的STAT3/ULBP2轴可能是提高CC中γ δ T细胞免疫治疗效率的潜在候选靶点。
Immunotherapy based on gamma delta T cells has limited efficiency in solid tumors, including colon cancer (CC). The immune evasion of tumor cells may be the main cause of the difficulties of gamma delta T cell-based treatment. In the present study, we explored whether and how B7-H3 regulates the resistance of CC cells to the cytotoxicity of V gamma 9V delta 2 (V delta 2) T cells. We observed that B7-H3 overexpression promoted, while B7-H3 knockdown inhibited, CC cell resistance to the killing effect of V delta 2 T cells in vitro and in vivo. Mechanistically, we showed that B7-H3-mediated CC cell resistance to the cytotoxicity of V delta 2 T cells involved a molecular pathway comprising STAT3 activation and decreased ULBP2 expression. ULBP2 blockade or knockdown abolished the B7-H3 silencing-induced increase in the cytotoxicity of V delta 2 T cells to CC cells. Furthermore, cryptotanshinone, a STAT3 phosphorylation inhibitor, reversed the B7-H3 overexpression-induced decrease in ULBP2 expression and attenuated the killing effect of V delta 2 T cells on CC cells. Moreover, there was a negative correlation between the expression of B7-H3 and ULBP2 in the tumor tissues of CC patients. Our results suggest that the B7-H3-mediated STAT3/ULBP2 axis may be a potential candidate target for improving the efficiency of gamma delta T cell-based immunotherapy in CC.