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

Abstract

Loss of IFN{gamma}-sensitivity by tumours is thought to be a mechanism enabling evasion, as some cancers lacking IFN{gamma}-signalling demonstrate resistance to checkpoint immunotherapy. However, recent studies demonstrated that IFN{gamma}-resistant tumours are well-controlled and sensitized for immunotherapy. The underlying mechanism leading to enhanced immune responses in those patients is unknown. Using IFN{gamma}-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 IFN{gamma} was still important for tumour control. Mechanistically, IFN{gamma} triggers pro-inflammatory remodelling of IFN{gamma}-insensitive tumours, affecting the differentiation of myeloid cells. Predominantly, immunosuppressive macrophages are inhibited, while inflammatory phenotypes of monocytes and mono-macs are preserved in IFN{gamma}-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 IFN{gamma} resistance does not preclude failure of anti-tumour responses. Importantly, immune remodelling appears to be dominant in IFN{gamma}-sensitive and IFN{gamma}-insensitive mixed tumours, and is enriched in humans with tumours mutated in the IFN{gamma} pathway, suggesting this may be leveraged for therapy in the future.