Follicular Regulatory T-cells Promote Cancer

滤泡调节性 T 细胞促进癌症

• 批准号: 10563684
• 负责人: Jianmei Wu Leavenworth
• 金额: $ 39.65万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-01 至 2027-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10563684
• 关键词: Acidity; Activities of Daily Living; Affinity; Antibody Response; B-Lymphocytes; Cancer Patient; Cell physiology; Cells; Clinical; Coupled; Deposition; Development; Economics; Evolution; FOXP3 gene; Flow Cytometry; Freezing; Frequencies; Goals; Human; Hydrogen; Hypoxia; IgE; Immune system; Immunofluorescence Immunologic; Impairment; Macrophage; Magnetic Resonance Imaging; Maintenance; Malignant Neoplasms; Mediating; Modeling; Mus; NHE1; Neoplasm Metastasis; Outcome; PD-1 blockade; PRDM1 gene; Peripheral Blood Mononuclear Cell; Population; Positron-Emission Tomography; Prognostic Marker; Public Health; Regulation; Regulatory T-Lymphocyte; Reporting; Repression; Risk; Role; Secondary to; Self Tolerance; Serum; Shapes; Sodium; Specimen; Stains; Structure of germinal center of lymph node; T-Lymphocyte Subsets; T-cell receptor repertoire; Testing; Tissues; Tumor Escape; Tumor Expansion; Tumor Immunity; Tumor Promotion; Tumor-Infiltrating Lymphocytes; Tumor-associated macrophages; Up-Regulation; X-Ray Computed Tomography; adaptive immunity; biobank; cancer immunotherapy; cell type; clinically significant; contrast enhanced; defined contribution; digital; effector T cell; fluorescence molecular tomography; immune checkpoint blockade; immunogenicity; improved; insight; melanoma; neoplasm immunotherapy; new therapeutic target; patient prognosis; predictive marker; programs; receptor; response; single-cell RNA sequencing; spatial relationship; tertiary lymphoid organ; therapeutically effective; therapy outcome; tomography; transcription factor; tumor; tumor growth; tumor immunology; tumor microenvironment; tumor progression

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.

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 我们正在剖析许多癌症中常见的免疫抑制肿瘤促进机制。 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 在这项提案中，我们通过靶向这些细胞来开发有效的治疗方法来治疗癌症。 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对癌症免疫治疗的反应有所改善。 TFR细胞和体液抗体反应调节抗肿瘤免疫和肿瘤进展 我们最近对 TFR 细胞的研究表明，这些细胞在体内积累。 小鼠和人类黑色素瘤需要 TFR 细胞在肿瘤中的功能稳定性和抑制活性。 Treg 细胞中转录因子 Blimp1 的缺失不仅会导致功能受损。 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 进一步分析显示，肿瘤 TFR 特征较高。 PRDM1表达表明各种癌症的恶性程度和转移风险增加。 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)。 研究结果使我们认为肿瘤内 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。 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 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。 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。