Regeneron Pharmaceuticals Inc., Tarrytown, NY 10591, USA.
Sci Immunol. 2020 Dec 18;5(54). doi: 10.1126/sciimmunol.abb9561.
Although T cell checkpoint inhibitors have transformed the treatment of cancer, the molecular determinants of tumor cell sensitivity to T cell-mediated killing need further elucidation. Here, we describe a mouse genome-scale CRISPR knockout screen that identifies tumor cell TNFα signaling as an important component of T cell-induced apoptosis, with NF-κB signaling and autophagy as major protective mechanisms. Knockout of individual autophagy genes sensitized tumor cells to killing by T cells that were activated via specific TCR or by a CD3 bispecific antibody. Conversely, inhibition of mTOR signaling, which results in increased autophagic activity, protected tumor cells from T cell killing. Autophagy functions at a relatively early step in the TNFα signaling pathway, limiting FADD-dependent caspase-8 activation. Genetic inactivation of tumor cell autophagy enhanced the efficacy of immune checkpoint blockade in mouse tumor models. Thus, targeting the protective autophagy pathway might sensitize tumors to T cell-engaging immunotherapies in the clinic.
虽然 T 细胞检查点抑制剂已经改变了癌症的治疗方法，但肿瘤细胞对 T 细胞介导的杀伤敏感性的分子决定因素仍需要进一步阐明。在这里，我们描述了一个小鼠全基因组规模的 CRISPR 敲除筛选，该筛选确定肿瘤细胞 TNFα 信号是 T 细胞诱导凋亡的重要组成部分，NF-κB 信号和自噬是主要的保护机制。单独敲除自噬基因会使肿瘤细胞对通过特异性 TCR 或 CD3 双特异性抗体激活的 T 细胞的杀伤变得敏感。相反，抑制 mTOR 信号，导致自噬活性增加，可保护肿瘤细胞免受 T 细胞杀伤。自噬在 TNFα 信号通路的相对早期发挥作用，限制 FADD 依赖性半胱天冬酶-8 的激活。肿瘤细胞自噬的基因失活增强了免疫检查点阻断在小鼠肿瘤模型中的疗效。因此，靶向保护性自噬途径可能会使肿瘤对临床中与 T 细胞结合的免疫疗法更加敏感。
