Genetic diversity of tumors with mismatch repair deficiency influences anti-PD-1 immunotherapy response

Rajarsi Mandal, Robert M. Samstein, Ken Wing Lee, Jonathan J. Havel, Hao Wang, Chirag Krishna, Erich Y. Sabio, Vladimir Makarov, Fengshen Kuo, Pedro Blecua, Apoorva T. Ramaswamy, Jennifer N. Durham, Bjarne Bartlett, Xiaoxiao Ma, Raghvendra Srivastava, Sumit Middha, Ahmet Zehir, Jaclyn F. Hechtman, Luc Gt Morris, Nils WeinholdNadeem Riaz, Dung T. Le, Luis A. Diaz, Timothy A. Chan

Research output: Contribution to journalArticle

Abstract

Tumors with mismatch repair deficiency (MMR-d) are characterized by sequence alterations in microsatellites and can accumulate thousands of mutations. This high mutational burden renders tumors immunogenic and sensitive to programmed cell death-1 (PD-1) immune checkpoint inhibitors. Yet, despite their tumor immunogenicity, patients with MMR-deficient tumors experience highly variable responses, and roughly half are refractory to treatment.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. The extent of response is particularly associated with the accumulation of insertion-deletion (indel) mutational load. 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.

Original languageEnglish (US)
Pages (from-to)485-491
Number of pages7
JournalScience
Volume364
Issue number6439
DOIs
StatePublished - 2019

ASJC Scopus subject areas

  • General

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