A DR5/Ligase 3-mediated feedback loop perpetuates immunogenicity in mismatch repair deficient colorectal cancer.

Abstract

Colorectal cancers (CRCs) with deficient DNA mismatch repair (dMMR) and microsatellite instability (MSI) are believed to be intrinsically immunogenic and respond more favorably to immune checkpoint inhibitor (ICI) therapy. However, a significant fraction of dMMR/MSI CRCs do not respond or eventually develop resistance to ICIs. The mechanisms underlying dMMR/MSI-associated immunogenicity is unclear. The aim of this study was to investigate the role and mechanism of MSI-induced antitumor immunity in CRCs. We used transplant syngeneic tumor models, immune cell co-culture assays, and air-liquid interface (ALI) culture of tumor-derived organoids to investigate the mechanism by which dMMR elicits an antitumor immune response. We also analyzed the gene expression databases of CRC cancer patients receiving ICI treatment. We found that inactivating Mlh1 causes endoplasmic reticulum (ER) stress and death receptor 5 (Dr5)-mediated apoptosis in syngeneic colorectal tumors. Sustained immune response against Mlh1-deficient tumors requires nuclear Ligase 3 (Lig3)-mediated release of extrachromosomal circular DNAs (eccDNAs) from apoptotic cells. A feedback Dr5/Lig3 amplification loop perpetuates apoptosis and immune cell activation in Mlh1-deficient syngeneic tumors. This feedback mechanism is critical for the response to ICI therapy in mice, which is supported by a significant association between DR5 or LIG3 expression and the efficacy of ICI therapy in cancer patients. Our results reveal a functional link between dMMR and antitumor immunity, which may be useful for improving ICI therapy in tumors with different MMR statuses.