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

Catherine S. Grasso, Jennifer Tsoi, Mykola Onyshchenko, Gabriel Abril-Rodriguez, Petra Ross-Macdonald, Megan Wind-Rotolo, Ameya Champhekar, Egmidio Medina, Davis Y. Torrejon, Daniel Sanghoon Shin, Phuong Tran, Yeon Joo Kim, Cristina Puig-Saus, Katie Campbell, Agustin Vega-Crespo, Michael Quist, Christophe Martignier, Jason J. Luke, Jedd D. Wolchok, Douglas B. JohnsonBartosz Chmielowski, F. Stephen Hodi, Shailender Bhatia, William Sharfman, Walter J. Urba, Craig L. Slingluff, Adi Diab, John B.A.G. Haanen, Salvador Martin Algarra, Drew M. Pardoll, Valsamo Anagnostou, Suzanne L. Topalian, Victor E. Velculescu, Daniel E. Speiser, Anusha Kalbasi, Antoni Ribas

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)500-515.e3
JournalCancer cell
Volume38
Issue number4
DOIs
StatePublished - Oct 12 2020

Keywords

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

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

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