ATM inhibition enhance antitumor immunity of CRC by activating cGAS/STING and NFκB/IRF1/NLRC5 pathway

Abstract

Abstract Backgroud Accumulating evidence supports the concept that DNA damage response (DDR) 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 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. There is still a vast research opportunity for ATM targeted inhibition in tumors. Methods ATM knockout and knockdown colorectal cancer cell lines were used to construct animal models and perform in vitro experiments. KU60019 targets ATM as a drug control. Immunohistochemistry and flow cytometry were used to examine the frequency and functional properties of immune cells in the tumor tissue and tumor-draining lymph nodes. The mechanism was investigated by siRNA, Western blot, immunofluorescence, real-time quantitative PCR and flow cytometry. Results Here, we found that either gene knockout or drug intervention, ATM inhibition activated the cGAS/STING pathway in cancer cells, and this effect could be amplified by radiation. In addition, ATM inhibition augmented MHC class I expression in cancer cells and this effect was amplified by radiation and IFNγ, thereby promoting CD8+ T cells to active and kill cancer cells. We found that ATM inhibition in CRC cells leads to activation of canonical NFκB pathway and non-canonical NFκB pathway. Activation of the NFκB pathway in ATM-inhibited cells activated IRF1/NLRC5 pathway, leading to upregulation of MHC class I expression, which was STING independent. Conclusions 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.