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

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

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.