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Published in Nature cancer - 01 Mar 2020

Thibaut R, Bost P, Milo I, Cazaux M, Lemaître F, Garcia Z, Amit I, Breart B, Cornuot C, Schwikowski B, Bousso P,

Link to Pubmed [PMID] – 32803171

Link to DOI [DOI] – 10.1038/s43018-020-0038-2

Nat Cancer 2020 Mar; 1(3): 302-314

The cytokine IFN-γ produced by tumor-reactive T cells is a key effector molecule with pleiotropic effects during anti-tumor immune responses. While IFN-γ production is targeted at the immunological synapse, its spatiotemporal activity within the tumor remains elusive. Here, we report that while 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-seq 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.

https://pubmed.ncbi.nlm.nih.gov/32803171