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 language | English |
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Pages (from-to) | 302-314 |
Number of pages | 13 |
Journal | Nature Cancer |
Volume | 1 |
Issue number | 3 |
DOIs | |
State | Published - Mar 2020 |
All Science Journal Classification (ASJC) codes
- Oncology
- Cancer Research