Conserved Interferon-γ Signaling Drives Clinical Response to Immune Checkpoint Blockade Therapy in Melanoma

Cancer Cell. 2020 Oct 12;38(4):500-515.e3. doi: 10.1016/j.ccell.2020.08.005. Epub 2020 Sep 10.

Abstract

We analyze the transcriptome of baseline and on-therapy tumor biopsies from 101 patients with advanced melanoma treated with nivolumab (anti-PD-1) alone or combined with ipilimumab (anti-CTLA-4). We find that T cell infiltration and interferon-γ (IFN-γ) signaling signatures correspond most highly with clinical response to therapy, with a reciprocal decrease in cell-cycle and WNT signaling pathways in responding biopsies. We model the interaction in 58 human cell lines, where IFN-γ in vitro exposure leads to a conserved transcriptome response unless cells have IFN-γ receptor alterations. This conserved IFN-γ transcriptome response in melanoma cells serves to amplify the antitumor immune response. Therefore, the magnitude of the antitumor T cell response and the corresponding downstream IFN-γ signaling are the main drivers of clinical response or resistance to immune checkpoint blockade therapy.

Keywords: RNA-seq; anti-CTLA-4; anti-PD-1; biopsies; clinical trial; immune checkpoint blockade; immune exclusion; interferon-γ; resistance; response; transcriptomics.

Publication types

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

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Cell Line
  • Cell Line, Tumor
  • Female
  • Gene Expression Profiling / methods
  • Humans
  • Immune Checkpoint Inhibitors / administration & dosage
  • Interferon-gamma / metabolism*
  • Interferon-gamma / pharmacology
  • Ipilimumab / administration & dosage
  • Male
  • Melanoma / drug therapy*
  • Melanoma / genetics
  • Melanoma / metabolism
  • Middle Aged
  • Nivolumab / administration & dosage
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / metabolism
  • T-Lymphocytes / pathology
  • Transcriptome / drug effects
  • Transcriptome / genetics
  • Young Adult

Substances

  • Immune Checkpoint Inhibitors
  • Ipilimumab
  • Nivolumab
  • Interferon-gamma