期刊
NATURE MEDICINE
卷 25, 期 12, 页码 1916-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41591-019-0654-5
关键词
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资金
- Adelson Medical Research Foundation
- Conquer Cancer Foundation
- Society for Immunotherapy of Cancers
- Damon Runyon Cancer Research Foundation
- BroadNext10
- National Institutes of Health [K08 CA234458, R01 CA227388, U01 CA233100, T32 GM008313]
- Deutsche Forschungsgemeinschaft (German Research Foundation) [SCHA 422/17-1, PA 2376/1-1, HO 6389/2-1 (KFO 337)]
- National Science Foundation [DGE1144152]
Immune-checkpoint blockade (ICB) has demonstrated efficacy in many tumor types, but predictors of responsiveness to anti-PD1 ICB are incompletely characterized. In this study, we analyzed a clinically annotated cohort of patients with melanoma (n = 144) treated with anti-PD1 ICB, with whole-exome and whole-transcriptome sequencing of pre-treatment tumors. We found that tumor mutational burden as a predictor of response was confounded by melanoma subtype, whereas multiple novel genomic and transcriptomic features predicted selective response, including features associated with MHC-I and MHC-II antigen presentation. Furthermore, previous anti-CTLA4 ICB exposure was associated with different predictors of response compared to tumors that were naive to ICB, suggesting selective immune effects of previous exposure to anti-CTLA4 ICB. Finally, we developed parsimonious models integrating clinical, genomic and transcriptomic features to predict intrinsic resistance to anti-PD1 ICB in individual tumors, with validation in smaller independent cohorts limited by the availability of comprehensive data. Broadly, we present a framework to discover predictive features and build models of ICB therapeutic response.
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