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 Weinhold; Nadeem Riaz; Dung T. Le; Luis A. Diaz; Timothy A. Chan

doi:10.1126/science.aau0447

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

School of Medicine

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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.

Original language	English (US)
Pages (from-to)	485-491
Number of pages	7
Journal	Science
Volume	364
Issue number	6439
DOIs	https://doi.org/10.1126/science.aau0447
State	Published - 2019

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Mandal, R., Samstein, R. M., Lee, K. W., Havel, J. J., Wang, H., Krishna, C., Sabio, E. Y., Makarov, V., Kuo, F., Blecua, P., Ramaswamy, A. T., Durham, J. N., Bartlett, B., Ma, X., Srivastava, R., Middha, S., Zehir, A., Hechtman, J. F., Morris, L. G., ... Chan, T. A. (2019). Genetic diversity of tumors with mismatch repair deficiency influences anti-PD-1 immunotherapy response. Science, 364(6439), 485-491. https://doi.org/10.1126/science.aau0447

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 T.; Diaz, Luis A.; Chan, Timothy A.

In: Science, Vol. 364, No. 6439, 2019, p. 485-491.

Research output: Contribution to journal › Article › peer-review

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, DT, Diaz, LA & Chan, TA 2019, 'Genetic diversity of tumors with mismatch repair deficiency influences anti-PD-1 immunotherapy response', Science, 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 T. ; Diaz, Luis A. ; Chan, Timothy A. / Genetic diversity of tumors with mismatch repair deficiency influences anti-PD-1 immunotherapy response. In: Science. 2019 ; Vol. 364, No. 6439. pp. 485-491.

@article{92a85c090fb644f6877826cd30399440,

title = "Genetic diversity of tumors with mismatch repair deficiency influences anti-PD-1 immunotherapy response",

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.",

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

note = "Funding Information: This work was funded in part by NIH grant T32 CA009685 (R.M.), ASCO Conquer Cancer Foundation Young Investigator Award (R.M.), the Pershing Square Sohn Cancer Research Alliance (T.A.C.), the STARR Cancer Consortium (T.A.C.), the NIH (core grant 5P30 CA008748-50), Stand Up 2 Cancer (T.A.C.), NIH R35 CA232097 (T.A.C.), and NIH 1R01CA205426 (T.A.C.). Publisher Copyright: {\textcopyright} 2019 American Association for the Advancement of Science. All rights reserved.",

year = "2019",

doi = "10.1126/science.aau0447",

language = "English (US)",

volume = "364",

pages = "485--491",

journal = "Science",

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T1 - Genetic diversity of tumors with mismatch repair deficiency influences anti-PD-1 immunotherapy response

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 T.

AU - Diaz, Luis A.

AU - Chan, Timothy A.

N1 - Funding Information: This work was funded in part by NIH grant T32 CA009685 (R.M.), ASCO Conquer Cancer Foundation Young Investigator Award (R.M.), the Pershing Square Sohn Cancer Research Alliance (T.A.C.), the STARR Cancer Consortium (T.A.C.), the NIH (core grant 5P30 CA008748-50), Stand Up 2 Cancer (T.A.C.), NIH R35 CA232097 (T.A.C.), and NIH 1R01CA205426 (T.A.C.). Publisher Copyright: © 2019 American Association for the Advancement of Science. All rights reserved.

PY - 2019

Y1 - 2019

N2 - 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.

AB - 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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DO - 10.1126/science.aau0447

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AN - SCOPUS:85065567185

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JO - Science

JF - Science

SN - 0036-8075

IS - 6439

ER -

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

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