What drives this variable response is largely unknown, and a more granular understanding of the mechanistic nature of PD-1 inhibitor sensitivity in MMR-d tumors may help to more precisely inform their use across human cancers. Moreover, many MMR-d tumors fail to respond to anti–PD-1 therapy, and the proportion that are sensitive display a wide diversity of clinical benefit. However, MSI tumors include lesions with substantial genomic variation. These findings have led to the first tissue-agnostic approval for anti–PD-1 therapy across unresectable or metastatic solid tumors with microsatellite instability (MSI) or MMR-d ( 7). Recent work has demonstrated a high objective response rate (ORR 53%) to anti–PD-1 (programmed cell death–1) therapy across mismatch repair–deficient (MMR-d) solid tumors ( 5, 6).

Tumors with high microsatellite instability (MSI-H) accumulate substantial numbers of somatic mutations secondary to deficits in DNA mismatch repair (MMR) ( 4). Tumor mutational burden has been shown to strongly correlate with clinical response to immunotherapy using checkpoint inhibitors ( 1– 3). This study provides a rationale for the genome-wide characterization of MSI intensity and mutational load to better profile responses to anti–PD-1 immunotherapy across MMR-deficient human cancers. The extent of response is particularly associated with the accumulation of insertion-deletion (indel) mutational load. We present experimental and clinical evidence showing that the degree of microsatellite instability (MSI) and resultant mutational load, in part, underlies the variable response to PD-1 blockade immunotherapy in MMR-d human and mouse tumors. Yet, despite their tumor immunogenicity, patients with MMR-deficient tumors experience highly variable responses, and roughly half are refractory to treatment. This high mutational burden renders tumors immunogenic and sensitive to programmed cell death–1 (PD-1) immune checkpoint inhibitors. Tumors with mismatch repair deficiency (MMR-d) are characterized by sequence alterations in microsatellites and can accumulate thousands of mutations.

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