Bystander IFN-γ activity promotes widespread and sustained cytokine signaling altering the tumor microenvironment

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Thibaut, Ronan | Bost, Pierre | Milo, Idan | Cazaux, Marine | Lemaître, Fabrice | Garcia, Zacarias | Amit, Ido | Breart, Béatrice | Cornuot, Clémence | Schwikowski, Benno | Bousso, Philippe

Edité par CCSD ; Nature Research -

International audience. The cytokine interferon (IFN)-γ produced by tumor-reactive T cells is a key effector molecule with pleiotropic effects during anti-tumor immune responses. Although IFN-γ production is targeted at the immunologic synapse, its spatiotemporal activity within the tumor remains elusive. In the present study, we report that, although IFN-γ secretion requires local antigen recognition, IFN-γ diffuses extensively to alter the tumor microenvironment in distant areas. Using intravital imaging and a reporter for STAT1 translocation, we provide evidence that T cells mediate sustained IFN-γ signaling in remote tumor cells. Furthermore, tumor phenotypic alterations required several hours of exposure to IFN-γ, a feature that disfavored local IFN-γ activity over diffusion and bystander activity. Finally, single-cell RNA-sequencing data from melanoma patients also suggested bystander IFN-γ activity in human tumors. Thus, tumor-reactive T cells act collectively to create large cytokine fields that profoundly modify the tumor microenvironment.

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