Hoekstra and Slagter et al. studied the spatiotemporal behaviors of CD8+ T cell-derived IFNγ and TNFα in the TME. Using a single-cell transcriptome-based approach designed to identify cytokines signals received over time, they showed in both humanized and syngeneic mouse models that IFNγ was the dominant modifier of the TME, acting globally, compared with TNFα, which had short-range effects. In addition, T cell-exposed tumors with a strong IFNγ profile had decreased expression of TGFβ-induced genes, indicative of TME remodeling, providing evidence that the approach could be useful to dissect local and global cytokine modulation in the TME.
Contributed by Katherine Turner
ABSTRACT: Cells in the tumor microenvironment (TME) influence each other through secretion and sensing of soluble mediators, such as cytokines and chemokines. While signaling of interferon γ (IFNγ) and tumor necrosis factor α (TNFα) is integral to anti-tumor immune responses, our understanding of the spatiotemporal behavior of these cytokines is limited. Here, we describe a single cell transcriptome-based approach to infer which signal(s) an individual cell has received. We demonstrate that, contrary to expectations, CD8+ T cell-derived IFNγ is the dominant modifier of the TME relative to TNFα. Furthermore, we demonstrate that cell pools that show abundant IFNγ sensing are characterized by decreased expression of transforming growth factor β (TGFβ)-induced genes, consistent with IFNγ-mediated TME remodeling. Collectively, these data provide evidence that CD8+ T cell-secreted cytokines should be categorized into local and global tissue modifiers, and describe a broadly applicable approach to dissect cytokine and chemokine modulation of the TME.