Distinct spatiotemporal dynamics of CD8+ T cell-derived cytokines in the tumor microenvironment (7296)
Tumors consist of a dynamic collection of interacting tumor cells, stromal cells and immune cells. In addition to the direct cell-cell interactions that are mediated by receptor-ligand interactions, cells in the tumor microenvironment (TME) influence each other through the secretion and sensing of soluble mediators, such as cytokines and chemokines. While signaling of the interferon ? (IFN?) and tumor necrosis factor a (TNFa) cytokines has been shown to be critical in anti-tumor immune responses in a number of settings, our understanding of the spatiotemporal behavior of these cytokines in the TME is limited. Here, we describe a single cell transcriptome-based approach to infer which single or combined signals an individual cell has received and estimate the timing of such exposure. Using this technology, we demonstrate that, contrary to expectations, CD8+ T cell-derived IFN? is the dominant modifier of the TME relative to TNFa. Furthermore, we demonstrate that cell pools that show abundant IFN? sensing are characterized by decreased TGFß signaling, consistent with IFN?-mediated remodeling of the TME. Collectively, these data provide evidence that CD8+ T cell-secreted cytokines should be distinguished into local and more global modifiers of tumor tissue, and describe a broadly applicable approach to dissect cytokine and chemokine modulation of the tumor microenvironment. Overall design: Murine NRAS mutated melanoma-cells (NMM) exposed to the cytokines IFNy, TGFb in different orders. For 4 different prestimulations (2, 6, 12, 24 hours of continuous stimululation), followed up by a second stimulation (IFNg, TGFb, mix or control) for 24h.