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

Ronan Thibaut, Pierre Bost, Idan Milo, Marine Cazaux, Fabrice Lemaitre, Zacarias Garcia, Ido Amit, Beatrice Breart, Clemence Cornuot, Benno Schwikowski, Philippe Bousso

Research output: Contribution to journalArticlepeer-review

Abstract

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

Original languageEnglish
Pages (from-to)302-314
Number of pages13
JournalNature Cancer
Volume1
Issue number3
DOIs
StatePublished - Mar 2020

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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