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-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.
Original language | English (US) |
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Pages (from-to) | 500-515.e3 |
Journal | Cancer cell |
Volume | 38 |
Issue number | 4 |
DOIs | |
State | Published - Oct 12 2020 |
Keywords
- RNA-seq
- anti-CTLA-4
- anti-PD-1
- biopsies
- clinical trial
- immune checkpoint blockade
- immune exclusion
- interferon-γ
- resistance
- response
- transcriptomics
ASJC Scopus subject areas
- Oncology
- Cancer Research