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

Julie M. Mazet, Jagdish N. Mahale, Orion Tong, Robert A. Watson, Ana Victoria Lechuga‐Vieco, Gabriela Pirgova, Vivian W. C. Lau, Moustafa Attar, Lada A. Koneva, Stephen N. Sansom, Benjamin P. Fairfax and Audrey Gérard ()
Additional contact information
Julie M. Mazet: University of Oxford
Jagdish N. Mahale: University of Oxford
Orion Tong: University of Oxford
Robert A. Watson: University of Oxford
Ana Victoria Lechuga‐Vieco: University of Oxford
Gabriela Pirgova: University of Oxford
Vivian W. C. Lau: University of Oxford
Moustafa Attar: University of Oxford
Lada A. Koneva: University of Oxford
Stephen N. Sansom: University of Oxford
Benjamin P. Fairfax: University of Oxford
Audrey Gérard: University of Oxford

Nature Communications, 2023, vol. 14, issue 1, 1-21

Abstract: Abstract IFNγ is an immune mediator with concomitant pro- and anti-tumor functions. Here, we provide evidence that IFNγ directly acts on intra-tumoral CD8 T cells to restrict anti-tumor responses. We report that expression of the IFNγ receptor β chain (IFNγR2) in CD8 T cells negatively correlates with clinical responsiveness to checkpoint blockade in metastatic melanoma patients, suggesting that the loss of sensitivity to IFNγ contributes to successful antitumor immunity. Indeed, specific deletion of IFNγR in CD8 T cells promotes tumor control in a mouse model of melanoma. Chronic IFNγ 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 IFNγ depletes stem-like T cells to restrict anti-tumor immunity. Targeting this pathway might represent an alternative strategy to enhance T cell-based therapies.

Date: 2023
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DOI: 10.1038/s41467-023-35948-9

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