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 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 (New York, N.Y.)
Volume364
Issue number6439
DOIs
StatePublished - May 3 2019

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Immunotherapy
Cell Death
Microsatellite Instability
Neoplasms
Tumor Burden
Microsatellite Repeats
Turcot syndrome
Genome
Mutation
Therapeutics

ASJC Scopus subject areas

  • General

Cite this

Genetic diversity of tumors with mismatch repair deficiency influences anti-PD-1 immunotherapy response. / Mandal, Rajarsi; Samstein, Robert M.; Lee, Ken Wing; Havel, Jonathan J.; Wang, Hao; Krishna, Chirag; Sabio, Erich Y.; Makarov, Vladimir; Kuo, Fengshen; Blecua, Pedro; Ramaswamy, Apoorva T.; Durham, Jennifer N.; Bartlett, Bjarne; Ma, Xiaoxiao; Srivastava, Raghvendra; Middha, Sumit; Zehir, Ahmet; Hechtman, Jaclyn F.; Morris, Luc Gt; Weinhold, Nils; Riaz, Nadeem; Le, Dung; Diaz, Luis A.; Chan, Timothy A.

In: Science (New York, N.Y.), Vol. 364, No. 6439, 03.05.2019, p. 485-491.

Research output: Contribution to journalArticle

Mandal, R, Samstein, RM, Lee, KW, Havel, JJ, Wang, H, Krishna, C, Sabio, EY, Makarov, V, Kuo, F, Blecua, P, Ramaswamy, AT, Durham, JN, Bartlett, B, Ma, X, Srivastava, R, Middha, S, Zehir, A, Hechtman, JF, Morris, LG, Weinhold, N, Riaz, N, Le, D, Diaz, LA & Chan, TA 2019, 'Genetic diversity of tumors with mismatch repair deficiency influences anti-PD-1 immunotherapy response', Science (New York, N.Y.), vol. 364, no. 6439, pp. 485-491. https://doi.org/10.1126/science.aau0447
Mandal, Rajarsi ; Samstein, Robert M. ; Lee, Ken Wing ; Havel, Jonathan J. ; Wang, Hao ; Krishna, Chirag ; Sabio, Erich Y. ; Makarov, Vladimir ; Kuo, Fengshen ; Blecua, Pedro ; Ramaswamy, Apoorva T. ; Durham, Jennifer N. ; Bartlett, Bjarne ; Ma, Xiaoxiao ; Srivastava, Raghvendra ; Middha, Sumit ; Zehir, Ahmet ; Hechtman, Jaclyn F. ; Morris, Luc Gt ; Weinhold, Nils ; Riaz, Nadeem ; Le, Dung ; Diaz, Luis A. ; Chan, Timothy A. / Genetic diversity of tumors with mismatch repair deficiency influences anti-PD-1 immunotherapy response. In: Science (New York, N.Y.). 2019 ; Vol. 364, No. 6439. pp. 485-491.
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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.",
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AU - Mandal, Rajarsi

AU - Samstein, Robert M.

AU - Lee, Ken Wing

AU - Havel, Jonathan J.

AU - Wang, Hao

AU - Krishna, Chirag

AU - Sabio, Erich Y.

AU - Makarov, Vladimir

AU - Kuo, Fengshen

AU - Blecua, Pedro

AU - Ramaswamy, Apoorva T.

AU - Durham, Jennifer N.

AU - Bartlett, Bjarne

AU - Ma, Xiaoxiao

AU - Srivastava, Raghvendra

AU - Middha, Sumit

AU - Zehir, Ahmet

AU - Hechtman, Jaclyn F.

AU - Morris, Luc Gt

AU - Weinhold, Nils

AU - Riaz, Nadeem

AU - Le, Dung

AU - Diaz, Luis A.

AU - Chan, Timothy A.

PY - 2019/5/3

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