Remodelling of the immune landscape by IFNγ counteracts IFNγ-dependent tumour escape in mouse tumour models

Vivian W. C. Lau, Gracie J. Mead, Zofia Varyova, Julie M. Mazet, Anagha Krishnan, Edward W. Roberts, Gennaro Prota, Uzi Gileadi, Kim S. Midwood, Vincenzo Cerundolo and Audrey Gérard ()
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Vivian W. C. Lau: University of Oxford
Gracie J. Mead: University of Oxford
Zofia Varyova: University of Oxford
Julie M. Mazet: University of Oxford
Anagha Krishnan: University of Oxford
Edward W. Roberts: CRUK Beatson Institute
Gennaro Prota: University of Oxford
Uzi Gileadi: University of Oxford
Kim S. Midwood: University of Oxford
Vincenzo Cerundolo: University of Oxford
Audrey Gérard: University of Oxford

Nature Communications, 2025, vol. 16, issue 1, 1-19

Abstract: Abstract Loss of IFNγ-sensitivity by tumours is thought to be a mechanism enabling evasion, but recent studies suggest that IFNγ-resistant tumours can be sensitised for immunotherapy, yet the underlying mechanism remains unclear. Here, we show that IFNγ receptor-deficient B16-F10 mouse melanoma tumours are controlled as efficiently as WT tumours despite their lower MHC class I expression. Mechanistically, IFNγ receptor deletion in B16-F10 tumours increases IFNγ availability, triggering a remodelling of the immune landscape characterised by inflammatory monocyte infiltration and the generation of ‘mono-macs’. This altered myeloid compartment synergises with an increase in antigen-specific CD8+ T cells to promote anti-tumour immunity against IFNγ receptor-deficient tumours, with such an immune crosstalk observed around blood vessels. Importantly, analysis of transcriptomic datasets suggests that similar immune remodelling occurs in human tumours carrying mutations in the IFNγ pathway. Our work thus serves mechanistic insight for the crosstalk between tumour IFNγ resistance and anti-tumour immunity, and implicates this regulation for future cancer therapy.

Date: 2025
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DOI: 10.1038/s41467-024-54791-0

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