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

ABSTRACT: The cytokine IFN-? produced by tumor-reactive T cells is a key effector molecule with pleiotropic effects during anti-tumor immune responses. While IFN-? production is targeted at the immunological synapse, its spatiotemporal activity within the tumor remains elusive. Here, we report that while IFN-? secretion requires local antigen recognition, IFN-? 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-? signaling in remote tumor cells. Furthermore, tumor phenotypic alterations required several hours of exposure to IFN-?, a feature that disfavored local IFN-? activity over diffusion and bystander activity. Finally, single-cell RNA-seq data from melanoma patients also suggested bystander IFN-? activity in human tumors. Thus, tumor-reactive T cells act collectively to create large cytokine fields that profoundly modify the tumor microenvironment.

SUBMITTER: Thibaut R 

PROVIDER: S-EPMC7115926 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature