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

Nat Med. 2019 Dec;25(12):1916-1927. doi: 10.1038/s41591-019-0654-5. Epub 2019 Dec 2.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Antibodies, Monoclonal, Humanized / administration & dosage
  • Antigen Presentation / genetics
  • Antigen Presentation / immunology
  • CTLA-4 Antigen / antagonists & inhibitors
  • CTLA-4 Antigen / immunology*
  • Drug Resistance, Neoplasm / genetics
  • Female
  • Humans
  • Male
  • Melanoma / drug therapy*
  • Melanoma / genetics*
  • Melanoma / immunology
  • Melanoma / pathology
  • Mutation / genetics
  • Neoplasm Metastasis
  • Nivolumab / administration & dosage
  • Programmed Cell Death 1 Receptor / antagonists & inhibitors
  • Programmed Cell Death 1 Receptor / immunology*
  • Transcriptome / genetics
  • Transcriptome / immunology
  • Whole Exome Sequencing

Substances

  • Antibodies, Monoclonal, Humanized
  • CTLA-4 Antigen
  • CTLA4 protein, human
  • PDCD1 protein, human
  • Programmed Cell Death 1 Receptor
  • Nivolumab
  • pembrolizumab