Abstract 1622: Microsatellite instability causes colorectal cancer cell death to trigger anti-tumor immune response

Colorectal cancer (CRC) is the second leading cause of cancer deaths in the western world. Approximately 15% of CRCs have defects in DNA mismatch repair (MMR) genes, which lead to frequent mutations in repetitive genomic sequences known as microsatellites. This kind of genomic instability, referred to as microsatellite instability (MSI), contributes to the emergence of highly immunogenic neoantigen peptides that can stimulate an antitumor response. As such, a subset of CRC patients with deficient MMR has a positive response to immune checkpoint blockade immunotherapy. However, the molecular basis of MSI-induced antitumor immune response is not well understood. To address this issue, we used CRISPR to genetically inactivate MutL homolog 1 (MLH1), a key MMR protein, in two microsatellite stable (MSS) murine colorectal cancer cell lines, CT26 and MC-38, which enabled us to directly compare isogenic MSI and MSS tumors in mice with an immuno-deficient or -competent microenvironment. The growth of MLH1-KO cells was comparable to the parental cells in immunocompromised mice. Upon transplantation into syngeneic, immunocompetent mice, the parental CT26 and MC-38 tumors rapidly proliferate. In contrast, the MLH1-KO tumors grew poorly under the same conditions, which was accompanied by apoptotic cell death, upregulation of inflammatory cytokines, and tumor infiltration of CD8+ T lymphocytes. Blocking apoptosis by caspase inhibition suppressed cytokine induction and T lymphocyte infiltration, suggesting a key role of apoptosis in triggering an antitumor immune response. Our current efforts are towards elucidating the mechanism of cell death and defining the associated immune signatures. Ultimately, a better understanding of the immunological consequences of MSI status in CRCs may help to develop more effective CRC therapies. Citation Format: Darleny Y. Lizardo, Yi-Jun Wang, Liheng Yang, Jian Yu, Lin Zhang. Microsatellite instability causes colorectal cancer cell death to trigger anti-tumor immune response [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1622.