Biology subjects

Mazet, J. M.

Publications and source records attributed to Mazet, J. M..

2 recordsLinked to original sources

bioRxiv2024

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

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.

immunology↗

bioRxiv2023

Integration of Avidity and Differentiation is enabled by CD8+ T-cell sensing of IFN-γ

The most effective responses to intracellular pathogens have a breadth of T-cell clones with different affinities for their cognate peptide, and a diversity of functional phenotypes, from effector to long-lived memory cells. While high- and low-affinity T-cells are inherently skewed towards becoming effector and memory, respectively, overall, both functional subsets exploit a wide range of affinities. How the breadth of affinities and functionalities are coordinated is therefore unclear. In this study, we provide evidence that direct sensing of the cytokine IFN-{gamma} by CD8+ T-cells is a factor controlling the integration of T-cell affinity and differentiation during infection. IFN-{gamma} increases the expansion of low-affinity T-cells, allowing them to overcome the selective advantage of high-affinity T-cells. Concomitantly, IFN-{gamma} reinforces high-affinity T-cell entry into the memory pool. As a result, direct IFN-{gamma} sensing by CD8+ T-cells increases the avidity of the memory response. This comes at the expense of the primary T-cell response, for which IFN-{gamma} decreases the avidity, leading to sub-optimum immunity to infection. IFN-{gamma} sensing by CD8+ T-cells is paracrine, provided by a distinct subset of CD8+ T-cells called Virtual Memory T-cells, an antigen inexperienced subset that harbors memory features. Overall, we propose that IFN-{gamma} and Virtual Memory T-cells fulfil a critical immunoregulatory role by enabling the coordination of T-cell avidity and fate.

immunology↗