Genetic Diversity of Tumors with Mismatch Repair Deficiency Influences Tumor Evolution and Response to PD-1 Blockade

Tumors with mismatch repair deficiency (MMR-d) are characterized by sequence alterations in microsatellites and can accumulate thousands of mutations across the genome. This high mutational burden renders these tumors immunogenic and sensitive to PD-1 blockade. However, despite the immunogenicity of these tumors, clinical responses are highly variable, and many patients with MMR-d tumors do not benefit. The determinants of variable response in these tumors remain ill-defined. In this report, we present experimental and clinical evidence demonstrating that this variation is, in part, due to differences in the microsatellite instability (MSI) intensity and resultant mutational accumulation by MMR-d tumors. The intensity of the MSI phenotype dictates response to PD-1 blockade in both murine models and in treated patients. The extent of response is strongly associated with the number of missense and to a greater degree, insertion-deletion (indel) mutations. Furthermore, MMR-d mouse tumors undergo selective immunoediting of subclonal indel and missense mutations in response to PD-1 blockade. This study provides rationale for the genome-wide characterization of mutational burden and MSI intensity to better predict response to PD-1 blockade across MMR-deficient human cancers.