Champhekar, A. (Ameya)

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    Conserved interferon-g signaling drives clinical response to immune checkpoint blockade therapy in melanoma
    (Elsevier, 2020) Vega-Crespo, A. (Agustin); Kalbasi, A. (Anusha); Onyshchenko, M. (Mykola); Grasso, C.S. (Catherine S.); Speiser, D.E. (Daniel E.); Wind-Rotolo, M. (Megan); Ribas, A. (Antoni); Ross-Macdonald, P. (Petra); Diab, A. (Adi); Martin-Algarra, S. (Salvador); Sanghoon-Shin, D. (Daniel); Urba, W.J. (Walter J.); Campbell, K. (Katie); Champhekar, A. (Ameya); Medina, E. (Egmidio); Hodi, F.S. (F. Stephen); Johnson, D.B. (Douglas B.); Anagnostou, V. (Valsamo); Luke, J.J. (Jason J.); Tsoi, J. (Jennifer); Haanen, J. (J.); Tran, P. (Phuong); Velculescu, V.E. (Victor E.); Bhatia, S. (Shailender); Wolchok, J.D. (Jedd D.); Abril-Rodriguez, G. (Gabriel); Topalian, S.L. (Suzanne L.); Chmielowski, B. (Bartosz); Puig-Saus, C. (Cristina); Torrejon, D.Y. (Davis Y.); Joo-Kim, Y. (Yeon); Quist, M. (Michael); Martignier, C. (Christophe); Sharfman, W. (William); Slingluff, C.L. (Craig L.); Pardoll, D.M. (Drew M.)
    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.