肿瘤细胞治疗研究
英文原题：A CRISPR activation screen identifies MUC-21 as critical for resistance to NK and T cell-mediated cytotoxicity.
这些发现表明，表面 MUC21 是一种强效免疫抑制配体，可保护癌细胞免受 NK 和 CD8⁺ T 细胞的攻击。
背景：免疫疗法显著推动了癌症治疗进展，但许多患者仍无应答，部分原因是肿瘤细胞利用免疫抑制机制逃避免疫系统识别和清除。肿瘤细胞可表达免疫抑制性配体以实现免疫逃逸，因此发现并表征新型免疫抑制配体，对开发更有效的抗癌疗法至关重要。方法：研究人员利用覆盖整个人类跨膜蛋白亚基因组的CRISPRa（CRISPR激活）文库开展功能获得筛选，以识别可抑制NK细胞介导细胞毒作用的表面分子。采用NK和T细胞介导的细胞毒实验验证MUC21的免疫抑制作用及机制，并利用生物信息学分析黏蛋白21（MUC21）对肿瘤免疫的临床意义。结果：遗传筛选显示，癌细胞表面表达MUC21可抑制NK细胞细胞毒活性和抗体依赖性细胞介导的细胞毒作用，但不影响补体依赖性细胞毒作用。MUC21表达还可通过阻碍抗原识别抑制T细胞活化，从而降低抗PD-L1免疫检查点抑制剂疗效。此外，MUC21表达也抑制CAR-T和CAR-NK细胞抗肿瘤功能。机制上，MUC21通过造成空间位阻，阻止癌细胞与免疫细胞相互作用，促进免疫逃逸。生物信息学分析显示，肺癌中MUC21表达升高，与细胞毒性免疫细胞浸润和活化减少相关。值得注意的是，抗PD-(L)1治疗无应答的非小细胞肺癌（NSCLC）肿瘤中MUC21表达高于应答肿瘤。结论：细胞表面MUC21是一种强效免疫抑制配体，可保护癌细胞免受NK和CD8+ T细胞攻击；抑制MUC21可能成为增强癌症免疫治疗的有前景策略。
BACKGROUND: Immunotherapy has significantly advanced cancer treatments, but many patients do not respond to it, partly due to immunosuppressive mechanisms used by tumor cells. These cells employ immunosuppressive ligands to evade detection and elimination by the immune system. Therefore, the discovery and characterization of novel immunosuppressive ligands that facilitate immune evasion are crucial for developing more potent anti-cancer therapies. METHODS: We conducted gain-of-function screens using a CRISPRa (CRISPR activation) library that covered the entire human transmembrane sub-genome to identify surface molecules capable of hindering NK-mediated cytotoxicity. The immunosuppressive role and mechanism of MUC21 were validated using NK and T cell mediated cytotoxicity assays. Bioinformatics tools were employed to assess the clinical implications of mucin-21 (MUC21) in cancer cell immunity. RESULTS: Our genetic screens revealed that MUC21 expression on cancer cell surfaces inhibits both the cytotoxic activity of NK cells and antibody-dependent cellular cytotoxicity, but not affecting complement-dependent cytotoxicity. Additionally, MUC21 expression hinders T cell activation by impeding antigen recognition, thereby diminishing the effectiveness of the immune checkpoint inhibitor, anti-PD-L1. Moreover, MUC21 expression suppress the antitumor function of both CAR-T cells and CAR-NK cells. Mechanistically, MUC21 facilitates immune evasion by creating steric hindrance, preventing interactions between cancer and immune cells. Bioinformatics analysis revealed elevated MUC21 expression in lung cancer, which correlated with reduced infiltration and activation of cytotoxic immune cells. Intriguingly, MUC21 expression was higher in non-small cell lung cancer (NSCLC) tumors that were non-responsive to anti-PD-(L)1 treatment compared to responsive tumors. CONCLUSIONS: These findings indicate that surface MUC21 serves as a potent immunosuppressive ligand, shielding cancer cells from NK and CD8 + T cell attacks. This suggests that inhibiting MUC21 could be a promising strategy to improve cancer immunotherapy.
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