Exploiting Genomic Instability to Improve Immunogenicity of Colorectal Cancer

Abstract

The vast majority of colorectal cancer patients (~85%) present with tumors that exhibit minimal immune cell infiltration and are consequently unresponsive to immunotherapy1. Therefore, it is crucial to develop strategies that enable these patients to benefit from immunotherapy by priming the immune system to recognize and attack cold tumors. We propose a strategy to induce tumor cell genomic instability to make immunologically unresponsive tumors sensitive to immune control. Tumor genomic instability leads to the mislocalization of nuclear chromosomal DNA into micronuclei that are extruded into the cytoplasm. Upon rupture of the fragile micronuclear envelope, the released chromosomal fragments activate innate immune nucleic acid sensors and trigger downstream inflammatory pathways that cause immunogenic cell death. In our studies, treatment with mitotic spindle checkpoint protein MPS1 inhibitor, BAY-1217389, did not enhance antitumor efficacy, due to the low basal expression of inflammation-related genes in tumor cells. However, by combining the MPS1 inhibitor with decitabine, a clinically approved DNA methyltransferase inhibitor that derepresses the expression of innate immune genes in murine models of colorectal cancer, tumor growth was controlled without systemic toxicity and the antitumor immune response to immunotherapy was enhanced. Our findings suggest that augmenting tumor genomic instability, coupled with a DNA hypomethylating drug decitabine, could improve colorectal cancer responsiveness to immunotherapy.