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

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. [Display omitted] •T cell-induced IFN-γ correlates the best to immune checkpoint blockade (ICB) therapy•Immune signatures increase in on-therapy patients regardless of response to therapy•ICB therapy decreases MYC and WNT signaling in patients with clinical response•IFN-γ exposure of melanoma cells leads to a conserved transcriptome signature Analyzing the transcriptome of biopsies of patients during immune checkpoint blockade therapy, Grasso et al. show that the increase of T cell infiltration and the downstream IFN-γ signaling drive clinical responses.