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Abstract
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-? (IFN-?) 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-? in vitro exposure leads to a conserved transcriptome response unless cells have IFN-? receptor alterations. This conserved IFN-? 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-? signaling are the main drivers of clinical response or resistance to immune checkpoint blockade therapy.
View details for DOI 10.1016/j.ccell.2020.08.005
View details for PubMedID 32916126
View details for PubMedCentralID PMC7872287