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Conserved Interferon-γ Signaling Drives Clinical Response to Immune Checkpoint Blockade Therapy in Melanoma.
Cancer cell
  • 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 Johnson
  • Bartosz Chmielowski
  • F Stephen Hodi
  • Shailender Bhatia
  • William Sharfman
  • Walter Urba, Earle A. Chiles Research Institute, Providence Cancer Center, Portland, OR, 97213, USA.
  • 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
Document Type
Publication Date

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.

Clinical Institute
Earle A. Chiles Research Institute
Citation Information
Catherine S Grasso, Jennifer Tsoi, Mykola Onyshchenko, Gabriel Abril-Rodriguez, et al.. "Conserved Interferon-γ Signaling Drives Clinical Response to Immune Checkpoint Blockade Therapy in Melanoma." Cancer cell (2020)
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