IFN-γ-related mRNA Profile Predicts Clinical Response to PD-1 Blockade

J Clin Invest. 2017 Aug 1;127(8):2930-2940. doi: 10.1172/JCI91190. Epub 2017 Jun 26.

Abstract

Programmed death-1-directed (PD-1-directed) immune checkpoint blockade results in durable antitumor activity in many advanced malignancies. Recent studies suggest that IFN-γ is a critical driver of programmed death ligand-1 (PD-L1) expression in cancer and host cells, and baseline intratumoral T cell infiltration may improve response likelihood to anti-PD-1 therapies, including pembrolizumab. However, whether quantifying T cell-inflamed microenvironment is a useful pan-tumor determinant of PD-1-directed therapy response has not been rigorously evaluated. Here, we analyzed gene expression profiles (GEPs) using RNA from baseline tumor samples of pembrolizumab-treated patients. We identified immune-related signatures correlating with clinical benefit using a learn-and-confirm paradigm based on data from different clinical studies of pembrolizumab, starting with a small pilot of 19 melanoma patients and eventually defining a pan-tumor T cell-inflamed GEP in 220 patients with 9 cancers. Predictive value was independently confirmed and compared with that of PD-L1 immunohistochemistry in 96 patients with head and neck squamous cell carcinoma. The T cell-inflamed GEP contained IFN-γ-responsive genes related to antigen presentation, chemokine expression, cytotoxic activity, and adaptive immune resistance, and these features were necessary, but not always sufficient, for clinical benefit. The T cell-inflamed GEP has been developed into a clinical-grade assay that is currently being evaluated in ongoing pembrolizumab trials.

Publication types

  • Clinical Trial, Phase I
  • Randomized Controlled Trial

MeSH terms

  • Antibodies, Monoclonal, Humanized / therapeutic use*
  • Antineoplastic Agents / therapeutic use*
  • B7-H1 Antigen / metabolism
  • Biopsy
  • Carcinoma / drug therapy
  • Carcinoma / immunology
  • Carcinoma, Non-Small-Cell Lung / drug therapy
  • Carcinoma, Non-Small-Cell Lung / immunology
  • Gene Expression Profiling*
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Immune System
  • Immunohistochemistry
  • Interferon-gamma / metabolism*
  • Lung Neoplasms / drug therapy
  • Lung Neoplasms / immunology
  • Melanoma / drug therapy
  • Melanoma / immunology
  • Pilot Projects
  • Programmed Cell Death 1 Receptor / antagonists & inhibitors*
  • Programmed Cell Death 1 Receptor / metabolism
  • ROC Curve
  • Sequence Analysis, RNA
  • Signal Transduction
  • Skin Neoplasms / drug therapy
  • Skin Neoplasms / immunology
  • Stomach Neoplasms / drug therapy
  • Stomach Neoplasms / immunology*
  • Treatment Outcome
  • Tumor Microenvironment

Substances

  • Antibodies, Monoclonal, Humanized
  • Antineoplastic Agents
  • B7-H1 Antigen
  • CD274 protein, human
  • IFNG protein, human
  • PDCD1 protein, human
  • Programmed Cell Death 1 Receptor
  • Interferon-gamma
  • pembrolizumab