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Genetic Diversity of Tumors With Mismatch Repair Deficiency Influences anti-PD-1 Immunotherapy Response

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, etc.

Science. 2019 May 3;364(6439):485-491.

PMID: 31048490

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
IAR42411333	Ubiquitin-15N,D human			Price

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