Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
Department of Bioscience Technology, College of Health Science, Chang Jung Christian University, Tainan 711, Taiwan.
Cells. 2023 Apr 30;12(9):1288. doi: 10.3390/cells12091288.
Immune checkpoint blockade (ICB) therapy can improve the survival of cancer patients with a high tumor mutation burden (TMB-H) or deficiency in DNA mismatch repair (dMMR) in their tumors. However, most cancer patients without TMB-H and dMMR do not benefit from ICB therapy. The inhibition of ATM can increase DNA damage and activate the interferon response, thus modulating the tumor immune microenvironment (TIME) and the efficacy of ICB therapy. In this study, we showed that ATM inhibition activated interferon signaling and induced interferon-stimulated genes (ISGs) in cisplatin-resistant and parent cancer cells. The ISGs induced by ATM inhibition were correlated with survival in cancer patients who received ICB therapy. In oral cancer, high expressions of , , and were associated with low expressions of , the activation of inflamed immune pathways, and increased tumor-infiltrating scores of CD8+ T, natural killer, and dendritic cells. The high expressions of , , and were also correlated with complete remission in patients with cervical cancer treated with cisplatin. These results suggest that ATM inhibition can induce the interferon response and inflamed TIME, which may benefit ICB therapy.
免疫检查点阻断 (ICB) 疗法可以改善肿瘤突变负担高 (TMB-H) 或肿瘤中 DNA 错配修复缺陷 (dMMR) 的癌症患者的生存率。然而，大多数没有 TMB-H 和 dMMR 的癌症患者不能从 ICB 治疗中获益。ATM 的抑制可以增加 DNA 损伤并激活干扰素反应，从而调节肿瘤免疫微环境 (TIME) 和 ICB 治疗的疗效。在这项研究中，我们表明 ATM 抑制在顺铂耐药和亲本癌细胞中激活了干扰素信号，并诱导了干扰素刺激基因 (ISGs)。ATM 抑制诱导的 ISGs 与接受 ICB 治疗的癌症患者的生存相关。在口腔癌中，高表达 、 和 与低表达 、 、炎症免疫途径的激活以及 CD8+T、自然杀伤和树突状细胞浸润评分的增加相关。高表达 、 和 也与接受顺铂治疗的宫颈癌患者的完全缓解相关。这些结果表明，ATM 抑制可以诱导干扰素反应和炎症性 TIME，这可能有益于 ICB 治疗。
