Follicular Regulatory T-cells Promote Cancer

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Project Summary Efforts to amplify the body’s immune system against cancer has faced a barrier due to the body’s own immunosuppressive tumor-promoting mechanisms, as commonly present for many cancers. We are dissecting these shared mechanisms by focusing on specific immunosuppressive cells in the tumor with the goal of developing effective therapeutic approaches by targeting these cells to treat cancer. In this proposal, we investigate the potential tumor-promoting role of a specific regulatory T (Treg) cell subset, called follicular regulatory T (TFR) cells. TFR cells are known to regulate follicular helper T (TFH) cells, B-cells and germinal center (GC) antibody responses, while the intensity of TFH cells, B-cells and tertiary lymphoid structures (TLS) in many cancers predict improved clinical outcomes and responses to cancer immunotherapy. However, the contribution of TFR cells and humoral antibody responses to the regulation of anti-tumor immunity and tumor progression remains to be largely unexplored. Our recent study of TFR cells has revealed that these cells accumulate in murine and human melanoma. The functional stability and suppressive activity of TFR cells in the tumor require the expression of the transcription factor Blimp1. Deletion of Blimp1 in Treg cells not only results in impaired suppressive activity, but also leads to the expansion of TIL TFH cells and GC B-cells, and enhanced tumoral IgE deposition secondary to TFR dysregulation. Further analysis revealed that higher tumoral TFR signatures along with PRDM1 expression indicated increased malignancy and risk of metastasis in various cancers. Increased IgE was associated with the activation and polarization of tumor-associated macrophages (TAMs) via the IgE high affinity receptor FcεRIα, potentially remodeling the tumor microenvironment (TME). These unexpected findings lead us to hypothesize that intratumoral TFR cells negatively impact the TME and promote tumor progression by repressing IgE-mediated anti-tumor immunity, and disrupting intratumoral TFR suppressive activity improves tumor control. Using genetically-modified mice and various tumor models, we will define the functional capacity and mechanistic action of TFR cells in the regulation of tumor progression, define the contribution of IgE to anti-tumor immunity and the TME remodeling. Finally, we will validate the TFR-IgE/FCERIA axis in human tumors. Completion of this study will reveal the previously unappreciated cell type, TFR cells, as a cancer prognostic biomarker and the IgE response as a predictor to the TIL TFR cell function. Insights gained from this project will facilitate the identification of new therapeutic targets and predictive markers to therapeutic outcome, and the development of effective approaches to treat a broad spectrum of cancers.