Department of Genetics and Development, Columbia University Irving Medical Center, New York, NY 10032, USA; Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY 10032, USA.
Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY 10032, USA; Department of Systems Biology, Columbia University Irving Medical Center, New York, NY 10032, USA.
Cell. 2024 Feb 15;187(4):861-881.e32. doi: 10.1016/j.cell.2024.01.008. Epub 2024 Jan 31.
Genomic instability can trigger cancer-intrinsic innate immune responses that promote tumor rejection. However, cancer cells often evade these responses by overexpressing immune checkpoint regulators, such as PD-L1. Here, we identify the SNF2-family DNA translocase SMARCAL1 as a factor that favors tumor immune evasion by a dual mechanism involving both the suppression of innate immune signaling and the induction of PD-L1-mediated immune checkpoint responses. Mechanistically, SMARCAL1 limits endogenous DNA damage, thereby suppressing cGAS-STING-dependent signaling during cancer cell growth. Simultaneously, it cooperates with the AP-1 family member JUN to maintain chromatin accessibility at a PD-L1 transcriptional regulatory element, thereby promoting PD-L1 expression in cancer cells. SMARCAL1 loss hinders the ability of tumor cells to induce PD-L1 in response to genomic instability, enhances anti-tumor immune responses and sensitizes tumors to immune checkpoint blockade in a mouse melanoma model. Collectively, these studies uncover SMARCAL1 as a promising target for cancer immunotherapy.
基因组不稳定性可引发促进肿瘤排斥的固有内在免疫反应。然而，癌细胞常通过过表达免疫检查点调节剂（如 PD-L1）来逃避这些反应。在此，我们鉴定出 SNF2 家族 DNA 易位酶 SMARCAL1 是通过两种机制促进肿瘤免疫逃逸的一个因素，这两种机制涉及固有免疫信号的抑制和 PD-L1 介导的免疫检查点反应的诱导。在机制上，SMARCAL1 限制内源性 DNA 损伤，从而在癌细胞生长过程中抑制 cGAS-STING 依赖性信号传导。同时，它与 AP-1 家族成员 JUN 合作，维持 PD-L1 转录调控元件的染色质可及性，从而促进癌细胞中 PD-L1 的表达。SMARCAL1 的缺失会阻碍肿瘤细胞在基因组不稳定时诱导 PD-L1 的能力，增强抗肿瘤免疫反应，并在小鼠黑素瘤模型中使肿瘤对免疫检查点阻断更敏感。总的来说，这些研究揭示了 SMARCAL1 是癌症免疫治疗的一个有前途的靶点。
