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

• DOI: 10.1016/j.ccell.2020.08.005
• Publication Date: 2020-09-10T14:43:42Z
• Authors: Catherine S. Grasso; Jennifer Tsoi; Mykola Onyshchenko; Gabriel Abril-Rod...; 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 Martig...; Jason J. Luke; Jedd D. Wolchok; Douglas B. Johnson; Bartosz Chmielowski; F. Stephen Hodi; Shailender Bhatia; William Sharfman; Walter J. Urba; Craig L. Slingluff; Adi Diab; John B.A.G. Haanen; Salvador Martin A...; Drew M. Pardoll; Valsamo Anagnostou; Suzanne L. Topalian; Victor E. Velculescu; Daniel E. Speiser; Anusha Kalbasi; Antoni Ribas
• Keywords: Immune checkpoint

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.