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-Î³ (IFN-Î³) 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-Î³ in vitro exposure leads to a conserved transcriptome response unless cells have IFN-Î³ receptor alterations . This conserved IFN-Î³ 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-Î³ signaling are the main drivers of clinical response or resistance to immune checkpoint blockade therapy.