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Integrative molecular and clinical modeling of clinical outcomes to PD1 blockade in patients with metastatic melanoma.

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.

journal_name

Nat Med

journal_title

Nature medicine

authors

Liu D,Schilling B,Liu D,Sucker A,Livingstone E,Jerby-Arnon L,Zimmer L,Gutzmer R,Satzger I,Loquai C,Grabbe S,Vokes N,Margolis CA,Conway J,He MX,Elmarakeby H,Dietlein F,Miao D,Tracy A,Gogas H,Goldinger SM,Utikal J

doi

10.1038/s41591-019-0654-5

subject

Has Abstract

pub_date

2019-12-01 00:00:00

pages

1916-1927

issue

12

eissn

1078-8956

issn

1546-170X

pii

10.1038/s41591-019-0654-5

journal_volume

25

pub_type

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