Dual mechanism of immune escape shapes the genetic and immunogenic landscape of mismatch repair-deficient colorectal tumours.

Abstract

Mismatch repair-deficient (MMRd) colorectal cancers (CRCs) are highly mutated and immunogenic yet frequently escape immune elimination. To define how host immunity shapes the genomic architecture and tumour microenvironment of MMRd CRC. We used a genetically engineered mouse model of MMRd CRC to compare tumour development in immunocompetent and immunodeficient hosts. Tumours were characterised for microenvironment composition, immunoregulatory pathways, mutational burden and genetic diversity. Immunogenicity of selected mutations was tested and findings were validated in human samples. In immunocompetent hosts, immune pressure reduces tumour incidence through selective elimination of early neoplastic clones bearing immunogenic mutations, consistent with antigen-specific immunoediting. Tumours exhibit a suppressive microenvironment with reduced cytotoxic lymphocytes and elevated immune checkpoint proteins. Tumours from immunodeficient mice showed higher mutational burden, greater genetic diversity and enrichment of mutations absent in immunocompetent animals, several of which encode neoantigens that elicit CD8⁺ T cell responses. Analyses of human CRCs with high microsatellite instability (MSI-H) confirmed retention of the same immunogenic mutations, elevated mutational burden, reduced effector immune infiltration and expression of immune checkpoint proteins. These results support a dual mechanism of immune escape, immunoediting and local immunosuppression, allowing MMRd CRC tumours to persist despite immune recognition. We show that immunosurveillance plays a dual role in constraining tumour development and sculpting the genetic and immunological landscapes of MMRd tumours. This evasion strategy explains the paradox of immune-rich yet progressive MMRd tumours and highlights vulnerabilities that could be exploited by neoantigen-based or immune reactivation therapies.