Remodelling of the immune landscape by IFNγ counteracts IFNγ-dependent tumour escape in mouse tumour models
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 tumo...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-01-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-54791-0 |
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| author | 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 Audrey Gérard |
| author_facet | 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 Audrey Gérard |
| author_sort | Vivian W. C. Lau |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-29d0b4100063496a929b748090e9c890 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-29d0b4100063496a929b748090e9c8902025-01-05T12:38:27ZengNature PortfolioNature Communications2041-17232025-01-0116111910.1038/s41467-024-54791-0Remodelling of the immune landscape by IFNγ counteracts IFNγ-dependent tumour escape in mouse tumour modelsVivian W. C. Lau0Gracie J. Mead1Zofia Varyova2Julie M. Mazet3Anagha Krishnan4Edward W. Roberts5Gennaro Prota6Uzi Gileadi7Kim S. Midwood8Vincenzo Cerundolo9Audrey Gérard10The Kennedy Institute of Rheumatology, University of OxfordThe Kennedy Institute of Rheumatology, University of OxfordThe Kennedy Institute of Rheumatology, University of OxfordThe Kennedy Institute of Rheumatology, University of OxfordThe Kennedy Institute of Rheumatology, University of OxfordCRUK Beatson InstituteMRC Translational Immune Discovery Unit, John Radcliffe Hospital, University of OxfordMRC Translational Immune Discovery Unit, John Radcliffe Hospital, University of OxfordThe Kennedy Institute of Rheumatology, University of OxfordMRC Translational Immune Discovery Unit, John Radcliffe Hospital, University of OxfordThe Kennedy Institute of Rheumatology, University of OxfordAbstract 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.https://doi.org/10.1038/s41467-024-54791-0 |
| spellingShingle | 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 Audrey Gérard Remodelling of the immune landscape by IFNγ counteracts IFNγ-dependent tumour escape in mouse tumour models Nature Communications |
| title | Remodelling of the immune landscape by IFNγ counteracts IFNγ-dependent tumour escape in mouse tumour models |
| title_full | Remodelling of the immune landscape by IFNγ counteracts IFNγ-dependent tumour escape in mouse tumour models |
| title_fullStr | Remodelling of the immune landscape by IFNγ counteracts IFNγ-dependent tumour escape in mouse tumour models |
| title_full_unstemmed | Remodelling of the immune landscape by IFNγ counteracts IFNγ-dependent tumour escape in mouse tumour models |
| title_short | Remodelling of the immune landscape by IFNγ counteracts IFNγ-dependent tumour escape in mouse tumour models |
| title_sort | remodelling of the immune landscape by ifnγ counteracts ifnγ dependent tumour escape in mouse tumour models |
| url | https://doi.org/10.1038/s41467-024-54791-0 |
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