Integrative molecular and clinical modeling of clinical outcomes to PD1 blockade in patients with metastatic melanoma
Research output: Contribution to journal › Research article › Contributed › peer-review
Contributors
Abstract
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.
Details
Original language | English |
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Pages (from-to) | 1916-1927 |
Number of pages | 12 |
Journal | Nature medicine |
Volume | 25 |
Issue number | 12 |
Publication status | Published - 1 Dec 2019 |
Peer-reviewed | Yes |
External IDs
PubMed | 31792460 |
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ORCID | /0009-0001-4054-4024/work/155291690 |