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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