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 (New York, N.Y.) |
| Volume | 364 |
| Issue number | 6439 |
| DOIs | |
| State | Published - May 3 2019 |
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- 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 journal › Article
}
TY - JOUR
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
AU - Diaz, Luis A.
AU - Chan, Timothy A.
PY - 2019/5/3
Y1 - 2019/5/3
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.
UR - http://www.scopus.com/inward/record.url?scp=85065567185&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85065567185&partnerID=8YFLogxK
U2 - 10.1126/science.aau0447
DO - 10.1126/science.aau0447
M3 - Article
C2 - 31048490
AN - SCOPUS:85065567185
VL - 364
SP - 485
EP - 491
JO - Science
JF - Science
SN - 0036-8075
IS - 6439
ER -