Regulatory T Cells Impact the State of Key Tumor Microenvironment Cells

Regulatory T (T_reg) cells have immunosuppressive functions, and their depletion has been shown to restrain tumor growth across many cancer models. These cells have typically been shown to suppress antigen-presenting cells as well as effector T cells, but recent studies have indicated that a wider range of cell types may be affected by T_reg cell functions. To determine the connection between T_reg cells and other cell types within the tumor microenvironment (TME), Glasner, Rose, Sharma, and colleagues evaluated the immediate changes to the single-cell transcriptomes of accessory cells within the TME using temporally controlled deletion of T_reg cells in murine lung cancer models. Alterations to the transcriptional programs of endothelial cells, fibroblasts, and macrophages were observed 48 hours after T_reg depletion, and gene expression programs related to IFN response, inflammatory cytokines (IC), and IL6 signaling were shared between accessory cells. Moreover, similar phenotypes were observed in an injury model of fibrotic lung inflammation, suggesting that these phenotypes are shared across pathologic conditions. Evaluation of the spatial distribution of accessory cell types revealed two distinct signaling niches in the tissue, with the IC gene program being clustered to the tumor core, while the IFN response gene program was localized to the periphery of tumor lesions, supporting the notion that the response to T_reg depletion is spatially restricted. Additionally, T_reg cell–dependent gene expression patterns, including VEGF and CCR2 signaling–related genes, were found to be conserved between mouse and human lung adenocarcinoma, which highlighted compensatory pathways that could be potentially targeted along with T_reg depletion strategies. Accordingly, as proof of concept, depletion of T_reg cells in combination with a VEGF neutralizing antibody in murine lung tumor cells resistant to PD-1 blockade demonstrated greater tumor reduction and improved overall survival as compared to no treatment or either single agent alone. In summary, this study shows that T_reg cells impact many cells within the TME and suggests that targeting these interdependent networks can be exploited in the development of new therapeutic strategies.

Glasner A, Rose SA, Sharma R, Gudjonson H, Chu T, Green JA, et al. Conserved transcriptional connectivity of regulatory T cells in the tumor microenvironment informs new combination cancer therapy strategies. Nat Immunol 2023 May 1 [Epub ahead of print].

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