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


Authors: 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.; Weinhold, N.; Riaz, N.; Le, D. T.; Diaz, L. A. Jr; Chan, T. A.
Article 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. Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
Journal Title: Science
Volume: 364
Issue: 6439
ISSN: 0036-8075
Publisher: American Association for the Advancement of Science  
Date Published: 2019-05-03
Start Page: 485
End Page: 491
Language: English
DOI: 10.1126/science.aau0447
PUBMED: 31048490
PROVIDER: scopus
PMCID: PMC6685207
DOI/URL:
Notes: Article -- Export Date: 3 June 2019 -- Source: Scopus
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MSK Authors
  1. Timothy Chan
    271 Chan
  2. Nadeem Riaz
    271 Riaz
  3. Luc Morris
    158 Morris
  4. Ahmet Zehir
    227 Zehir
  5. Jaclyn Frances Hechtman
    171 Hechtman
  6. Vladimir Makarov
    44 Makarov
  7. Jonathan Joseph Havel
    16 Havel
  8. Sumit   Middha
    79 Middha
  9. Ken-Wing   Lee
    7 Lee
  10. Rajarsi   Mandal
    7 Mandal
  11. Erich Sabio
    3 Sabio
  12. Fengshen Kuo
    25 Kuo
  13. Luis Alberto Diaz
    50 Diaz
  14. Xiaoxiao Ma
    2 Ma