Follicular Regulatory T-cells Promote Cancer

项目概要 由于人体自身的原因，增强人体免疫系统对抗癌症的努力面临着障碍 免疫抑制肿瘤促进机制，如许多癌症中常见的那样。 We are dissecting 这些共同的机制通过关注肿瘤中的特定免疫抑制细胞来实现 通过靶向这些细胞来治疗癌症，开发有效的治疗方法。 In this proposal, we 研究称为滤泡的特定调节性 T (Treg) 细胞亚群的潜在促肿瘤作用 调节性 T (TFR) 细胞。 TFR 细胞已知可调节滤泡辅助 T (TFH) 细胞、B 细胞和生发中心 (GC) 抗体反应，而 TFH 细胞、B 细胞和三级淋巴结构 (TLS) 的强度在许多 癌症预测临床结果和癌症免疫治疗反应的改善。然而，贡献 TFR细胞和体液抗体反应调节抗肿瘤免疫和肿瘤进展 很大程度上仍有待探索。我们最近对 TFR 细胞的研究表明，这些细胞在 小鼠和人类黑色素瘤。 TFR细胞在肿瘤中的功能稳定性和抑制活性需要 转录因子Blimp1的表达。 Treg 细胞中 Blimp1 的缺失不仅会导致细胞功能受损 抑制活性，还会导致 TIL TFH 细胞和 GC B 细胞的扩增，并增强肿瘤 IgE TFR 失调继发的沉积。进一步分析表明，较高的肿瘤 TFR 特征 PRDM1 表达表明各种癌症的恶性程度和转移风险增加。增加 IgE 通过 IgE 与肿瘤相关巨噬细胞 (TAM) 的激活和极化相关 高亲和力受体 FcεRIα，有可能重塑肿瘤微环境 (TME)。 These unexpected 研究结果使我们推测肿瘤内 TFR 细胞会对 TME 产生负面影响并促进肿瘤生长 通过抑制 IgE 介导的抗肿瘤免疫和破坏瘤内 TFR 抑制来抑制肿瘤进展 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 细胞在肿瘤进展调节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 axis in human tumors.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 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。 Insights gained 该项目将有助于确定新的治疗靶点和治疗的预测标记 结果，以及开发治疗多种癌症的有效方法。

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.