CD317 mediates immunocytolysis resistance by RICH2/cytoskeleton-dependent membrane protection
CD317 mediates immunocytolysis resistance by RICH2/cytoskeleton-dependent membrane protection
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CD317 通过 RICH2/细胞骨架依赖性膜保护介导免疫细胞溶解抵抗
DOI：
10.1016/j.molimm.2020.11.002
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发表时间：
2021-01-01
影响因子：
3.6
通讯作者：
Wan, Xiaochun
中科院分区：
文献类型：
--
作者：
Cheng, Jian;Liu, Zhao;Wan, Xiaochun
免疫逃避是癌症的常见特征。旨在恢复或增强针对癌症的免疫反应的免疫疗法彻底改变了患者的治疗结果，但耐药机制仍不清楚。在此，我们报道 CD317 是一种具有独特拓扑结构的表面分子，双锚定在膜上，可保护肿瘤细胞免受免疫细胞溶解。肿瘤细胞中的 CD317 敲低会导致 NK 细胞或嵌合抗原受体修饰的 NK 细胞的攻击导致更严重的死亡。 CD317沉默的这种效果可能是肿瘤细胞对免疫杀伤的敏感性增加而不是加强免疫反应的结果，因为效应器-靶细胞接触和效应细胞的激活均不受影响，并且增强的细胞溶解作用也没有通过添加重组CD317蛋白而抵消。从机制上讲，CD317可能通过与RICH2的结合赋予肿瘤细胞更大的灵活性来调节细胞骨架，从而保护膜完整性免受穿孔素的影响，从而促进免疫细胞溶解反应中的存活。这些结果揭示了免疫细胞溶解抵抗的新机制，并表明 CD317 是一个有吸引力的靶标，可用于提高癌症免疫疗法的功效。
Immune evasion is a common hallmark of cancers. Immunotherapies that aim at restoring or increasing the immune response against cancers have revolutionized outcomes for patients, but the mechanisms of resistance remain poorly defined. Here, we report that CD317, a surface molecule with a unique topology that is double anchored into the membrane, protects tumor cells from immunocytolysis. CD317 knockdown in tumor cells renders more severe death in response to NK or chimeric antigen receptor-modified NK cells challenge. Such effects of CD317 silencing might be the results of increasing sensitivity of tumor cells to immune killing rather than strengthening immune response, since neither effector-target cell contact nor the activation of effector cells was affected, and the enhanced cytolysis was also not counteracted by the addition of recombinant CD317 proteins. Mechanistically, CD317 might endow tumor cells with more flexibility to modulate cytoskeleton through its association with RICH2, thereby protects membrane integrity against perforin and consequently promotes survival in response to immunocytolysis. These results reveal a new mechanism of immunocytolysis resistance and suggest CD317 as an attractive target which can be exploited for improving the efficacy of cancer immunotherapies.