Conserved interferon-γ signaling drives clinical response to immune checkpoint blockade therapy in melanoma
Cancer cell, 2020•cell.com
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 …
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 …
Summary
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.
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