Follicular Regulatory T-cells Promote Cancer

项目摘要 由于人体自身的原因，增强人体免疫系统抵御癌症的努力面临障碍 免疫抑制促进肿瘤的机制，通常存在于许多癌症中。我们正在解剖 这些共同的机制是通过关注肿瘤中特定的免疫抑制细胞来实现的 通过靶向这些细胞来开发有效的治疗方法来治疗癌症。在这项提案中，我们 研究一种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。已知TFR细胞调节卵泡辅助性T细胞、B细胞和生发中心 (GC)抗体反应，而许多TFH细胞、B细胞和三级淋巴结构(TLS)的强度 癌症预示着临床结果的改善和对癌症免疫治疗的反应。然而，这一贡献 TFR细胞和体液抗体对抗肿瘤免疫和肿瘤进展的调节作用 在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。肿瘤中TFR细胞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 抑制活性，但也导致TIL TFH细胞和GC B细胞的扩张，并增强肿瘤IgE 继发于转铁蛋白受体失调的沉积。进一步的分析表明，较高的肿瘤TFR信号 随着PRDM1表达的增加，各种癌症的恶性程度和转移风险增加。增加了 免疫球蛋白E与肿瘤相关巨噬细胞(TAMs)的激活和极化有关 高亲和力受体FcεRIα，有可能重塑肿瘤微环境。这些意想不到的 这些发现使我们假设肿瘤内的TFR细胞对TME产生负面影响，并促进肿瘤 抑制IgE介导的抗肿瘤免疫和阻断肿瘤内TFR抑制的进展 活动可以改善肿瘤控制。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在抗肿瘤免疫和TME重塑中的作用最后，我们将验证TFR-IgE/FCERIA 在人类肿瘤中的轴。这项研究的完成将揭示以前未被认识的细胞类型，TFR细胞，作为一种 肿瘤预后生物标记物和作为TIL TFR细胞功能预测因子的IgE反应。获得洞察力 该项目将有助于识别新的治疗靶点和预测标记物 结果，以及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.