Open AccessBystander IFN-γ activity promotes widespread and sustained cytokine signaling altering the tumor microenvironment
Author(s) -
Ronan Thibaut,
Pierre Bost,
Idan Milo,
Marine Cazaux,
Fabrice Lemaı̂tre,
Zacarias Garcia,
Ido Amit,
Béatrice Breart,
Clémence Cornuot,
Benno Schwikowski,
Philippe Bousso
Publication year - 2020
Publication title -
nature cancer
Language(s) - English
Resource type - Journals
ISSN - 2662-1347
DOI - 10.1038/s43018-020-0038-2
Subject(s) - tumor microenvironment , bystander effect , cytokine , biology , immune system , microbiology and biotechnology , immunological synapse , cancer research , immunology , t cell , t cell receptor
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.