Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade¶
Why this mattered¶
This paper helped establish a decisive shift from treating cancers primarily by tissue of origin to treating them by a shared molecular vulnerability. Le and colleagues showed that mismatch repair deficiency, and the resulting microsatellite instability and high mutational burden, could predict response to PD-1 blockade across many solid tumors, not only colorectal cancer. The key claim was not merely that immunotherapy worked in one cancer type, but that a tumor’s genomic repair defect could define an immunologically responsive class of disease independent of anatomical site.
That made a new clinical strategy possible: selecting patients for checkpoint blockade using a biomarker that cut across traditional oncology categories. The study directly supported the rationale for tumor-agnostic immunotherapy, most notably the 2017 FDA approval of pembrolizumab for unresectable or metastatic MSI-H or mismatch repair-deficient solid tumors, the first cancer drug approval based on a molecular feature rather than tumor location. It also gave mechanistic weight to the neoantigen model of immunotherapy response: cancers with many mutations can generate mutant peptides recognizable by T cells, and PD-1 blockade can release those T-cell responses.
Its influence extended beyond mismatch repair deficiency. The paper helped normalize biomarker-led basket trials, strengthened the link between tumor genomics and immuno-oncology, and shaped later work on tumor mutational burden, neoantigen prediction, and personalized cancer vaccines. It did not make tissue of origin irrelevant, and not all mutation-rich tumors respond equally, but it made clear that the immune visibility of a cancer could be an organizing principle for therapy.
Abstract¶
The genomes of cancers deficient in mismatch repair contain exceptionally high numbers of somatic mutations. In a proof-of-concept study, we previously showed that colorectal cancers with mismatch repair deficiency were sensitive to immune checkpoint blockade with antibodies to programmed death receptor-1 (PD-1). We have now expanded this study to evaluate the efficacy of PD-1 blockade in patients with advanced mismatch repair-deficient cancers across 12 different tumor types. Objective radiographic responses were observed in 53% of patients, and complete responses were achieved in 21% of patients. Responses were durable, with median progression-free survival and overall survival still not reached. Functional analysis in a responding patient demonstrated rapid in vivo expansion of neoantigen-specific T cell clones that were reactive to mutant neopeptides found in the tumor. These data support the hypothesis that the large proportion of mutant neoantigens in mismatch repair-deficient cancers make them sensitive to immune checkpoint blockade, regardless of the cancers' tissue of origin.
Related¶
- cite → PD-1 Blockade in Tumors with Mismatch-Repair Deficiency — The 2017 solid-tumor study extends the 2015 finding that mismatch-repair deficiency predicts response to PD-1 blockade.
- cite → PD-1 blockade induces responses by inhibiting adaptive immune resistance — The 2017 mismatch-repair paper builds on the mechanism that PD-1 blockade restores antitumor T-cell activity by inhibiting adaptive immune resistance.
- cite → Mutational landscape determines sensitivity to PD-1 blockade in non–small cell lung cancer — The 2017 mismatch-repair paper links high mutation burden from repair deficiency to the neoantigen sensitivity to PD-1 blockade shown in lung cancer.
- cite → A general method applicable to the search for similarities in the amino acid sequence of two proteins — The mismatch-repair study cites Needleman-Wunsch sequence alignment as a general method for comparing protein amino-acid sequences.
- enables ← A general method applicable to the search for similarities in the amino acid sequence of two proteins — Needleman-Wunsch sequence alignment made it possible to compare mismatch-repair genes and related protein sequences when characterizing repair-deficient tumors.