Follicular Regulatory T-cells Promote Cancer

项目摘要 增强人体免疫系统对抗癌症的努力面临着一个障碍， 免疫抑制性肿瘤促进机制，如许多癌症通常存在的。我们在解剖 这些共同的机制通过关注肿瘤中的特异性免疫抑制细胞， 通过靶向这些细胞来治疗癌症来开发有效的治疗方法。在本提案中，我们 研究一种特定的调节性T（Treg）细胞亚群（称为滤泡性T细胞亚群）的潜在肿瘤促进作用。 调节性T（TFR）细胞。已知TFR细胞调节滤泡辅助性T（TFH）细胞、B细胞和生发中心。 (GC)抗体反应，而在许多组织中TFH细胞，B细胞和三级淋巴结构（TLS）的强度 癌症预测改善的临床结果和对癌症免疫疗法的反应。然而，贡献 TFR细胞和体液抗体应答调节抗肿瘤免疫和肿瘤进展 仍有待进一步探索我们最近对TFR细胞的研究表明，这些细胞在 鼠和人黑素瘤。TFR细胞在肿瘤中的功能稳定性和抑制活性需要 转录因子Blimp 1的表达。Treg细胞中Blimp 1的缺失不仅会导致 抑制活性，而且还导致TIL TFH细胞和GC B细胞的扩增，以及增强的肿瘤IgE 沉积继发于TFR失调。进一步的分析显示，较高的肿瘤TFR信号沿着 PRDM 1的表达表明在各种癌症中恶性度和转移风险增加。增加 IgE通过IgE与肿瘤相关巨噬细胞（TAMs）的活化和极化相关 高亲和力受体FcεRIα，可能重塑肿瘤微环境（TME）。这些意外 这些发现使我们假设肿瘤内TFR细胞对TME产生负面影响， 通过抑制IgE介导的抗肿瘤免疫和破坏肿瘤内TFR抑制 活性改善肿瘤控制。使用转基因小鼠和各种肿瘤模型，我们将定义 TFR细胞在调节肿瘤进展中的功能能力和机制作用，定义了 IgE对抗肿瘤免疫和TME重塑的贡献。最后，我们将验证TFR-IgE/FCERIA 轴在人类肿瘤中的作用。这项研究的完成将揭示以前未被重视的细胞类型，TFR细胞，作为一种新的细胞类型。 癌症预后生物标志物和IgE反应作为TIL TFR细胞功能的预测因子。获得的见解 从这个项目将有助于确定新的治疗靶点和预测标志物，以治疗 结果，并开发有效的方法来治疗广泛的癌症。

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.