IFNγ signaling in cytotoxic T cells restricts anti-tumor responses by inhibiting the maintenance and diversity of intra-tumoral stem-like T cells

IFN gamma is an immune mediator with concomitant pro- and anti-tumor functions. Here, we provide evidence that IFN gamma directly acts on intra-tumoral CD8 T cells to restrict anti-tumor responses. We report that expression of the IFN gamma receptor beta chain (IFN gamma R2) in CD8 T cells negatively correlates with clinical responsiveness to checkpoint blockade in metastatic melanoma patients, suggesting that the loss of sensitivity to IFN gamma contributes to successful antitumor immunity. Indeed, specific deletion of IFN gamma R in CD8 T cells promotes tumor control in a mouse model of melanoma. Chronic IFN gamma inhibits the maintenance, clonal diversity and proliferation of stem-like T cells. This leads to decreased generation of T cells with intermediate expression of exhaustion markers, previously associated with beneficial anti-tumor responses. This study provides evidence of a negative feedback loop whereby IFN gamma depletes stem-like T cells to restrict anti-tumor immunity. Targeting this pathway might represent an alternative strategy to enhance T cell-based therapies. IFN-gamma is associated with the efficacy of anti-tumour immune responses, and both pro- and anti-tumour functions have been ascribed to this cytokine. Here, the authors demonstrate that IFN-gamma signalling inhibits the maintenance of stem-like T cells, thereby impairing anti-tumour immune responses.