IFNgamma-dependent remodelling of the myeloid landscape underlies control of IFNgamma-insensitive tumours

Loss of IFNgamma-sensitivity by tumours is thought to be a mechanism enabling evasion, as some cancers lacking IFNgamma-signalling demonstrate resistance to checkpoint immunotherapy. However, recent studies demonstrated that IFNgamma-resistant tumours are well-controlled and sensitized for immunotherapy. The underlying mechanism leading to enhanced immune responses in those patients is unknown. Using IFNgamma-insensitive melanoma tumours which were well-controlled by the endogenous anti-tumour response, we found that despite low basal MHC class I expression by tumours, CD8+ T cell infiltration was not hindered and, unexpectedly, their production of IFNgamma was still important for tumour control. Mechanistically, IFNgamma triggers pro-inflammatory remodelling of IFNgamma-insensitive tumours, affecting the differentiation of myeloid cells. Predominantly, immunosuppressive macrophages are inhibited, while inflammatory phenotypes of monocytes and 'mono-macs' are preserved in IFNgamma-insensitive tumours. This is supported by a co-dependency between CD8+ T cells and monocyte/macrophages, as depletion of one resulted in loss of the other. Our work demonstrates an important mechanistic understanding of how IFNgamma resistance does not preclude failure of anti-tumour responses. Importantly, immune remodelling appears to be dominant in IFNgamma-sensitive and IFNgamma-insensitive mixed tumours, and is enriched in humans with tumours mutated in the IFNgamma pathway, suggesting this may be leveraged for therapy in the future.