Bystander IFN-γ activity promotes widespread and sustained cytokine signaling altering the tumor microenvironment
Open Access
- 9 March 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature Cancer
- Vol. 1 (3), 302-314
- https://doi.org/10.1038/s43018-020-0038-2
Abstract
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.This publication has 45 references indexed in Scilit:
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