Using intravital microscopy and mosaic (antigen [Ag]+/Ag-) tumor models, Thibaut et al. investigated spatiotemporal effects of IFNγ in the TME. Following local antigen stimulation, IFNγ diffused and signaled extensively within the TME, affecting both tumor cells and TILs. In mosaic tumors, strong T cell-derived bystander IFNγ activity occurred in distant Ag- tumor cells, was dependent on the responding T cell concentration, and resulted in sustained STAT1 signaling. Single-cell RNAseq of human melanoma samples revealed an IFNγ signature in monocytes/macrophages, which significantly correlated with the number of IFNγ+CD8+ T cells.
Contributed by Katherine Turner
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.
Author Info:
Author Info:
