PDF(Pubmed)
Abstract：
Accumulating evidence supports the concept that DNA damage response targeted therapies can improve antitumor immune response by increasing the immunogenicity of tumor cells and improving the tumor immune microenvironment. Ataxia telangiectasia mutated (ATM) is a core component of the DNA repair system. Although the ATM gene has a significant mutation rate in many human cancers, including colorectal, prostate, lung, and breast, it remains understudied compared with other DDR-involved molecules such as PARP and ATR. Here, we found that either gene knockout or drug intervention, ATM inhibition activated the cGAS/STING pathway and augmented MHC class I in CRC cells, and these effects could be amplified by radiation. Furthermore, we found that MHC class I upregulation induced by ATM inhibition is dependent on the activation of the NFκB/IRF1/NLRC5 pathway and independent of STING. Animal experiments have shown increasing infiltration and cytotoxic function of T cells and better survival in ATM-deficient tumors. This work indicated that ATM nonsense mutation predicted the clinical benefits of radiotherapy combined with immune checkpoint blockade for patients with CRC. It also provides a molecular mechanism rationale for ATM-targeted agents for patients with CRC.
摘要：
越来越多的证据支持DNA损伤应答靶向治疗可以通过增加肿瘤细胞的免疫原性和改善肿瘤免疫微环境来提高抗肿瘤免疫应答的观点。共济失调毛细血管扩张突变（ATM）是DNA修复系统的核心组成部分。尽管ATM基因在许多人类癌症中具有显著的突变率,包括结直肠,前列腺,肺，和乳房，与PARP和ATR等其他DDR相关分子相比，它仍未得到充分研究。这里,我们发现基因敲除或药物干预，ATM抑制激活了cGAS/STING途径并增强了CRC细胞中的I类MHC,这些影响可以被辐射放大。此外，我们发现由ATM抑制诱导的MHCI类上调依赖于NFκB/IRF1/NLRC5途径的激活，而不依赖于STING。动物实验表明，在ATM缺陷型肿瘤中，T细胞的浸润和细胞毒性功能增加，存活率更好。这项工作表明，ATM无义突变预测了放疗联合免疫检查点阻断对CRC患者的临床益处。它还为CRC患者的ATM靶向药物提供了分子机制原理。
