Regulatory T cells and the tumor microenvironment

调节性T细胞和肿瘤微环境

• 批准号: 10454307
• 负责人: Dario AA Vignali
• 金额: $ 90.64万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10454307
• 关键词: Ablation; Autoimmune; Cancer Model; Cells; Clinic; Development; Disease; Dissection; Goals; Immune; Immunity; Immunology; Immunotherapeutic agent; Interleukins; Malignant Neoplasms; Modality; NRP1 gene; Nature; Paper; Patients; Phase; Regulatory T-Lymphocyte; Reporting; Research; Science; Seminal; Therapeutic; Therapeutic Intervention; Translations; Tumor Immunity; Work; anticancer research; cancer clinical trial; cancer immunotherapy; cancer therapy; cell type; cytokine; immunoregulation; improved; inhibitor; novel; novel strategies; novel therapeutics; programs; receptor; therapy outcome; tumor; tumor immunology; tumor microenvironment

PROJECT SUMMARY I have been dissecting the mechanisms of immune regulation for ~27 years, and have been discovering and dissecting immune inhibitory mechanisms in cancer for over 10 years. Cancer immunology and immunotherapy now occupy ~80% of my research and translational focus. This has not only led to numerous cancer-focused high impact papers (11; Nature [1], Cell [1], Nature Immunology [4], Immunity [3], Science Immunology [1]; Cancer Research [1]), with 5 since 2016, but has also facilitated the development of immunotherapeutics targeting LAG3, EBI3 and NRP1 in multiple cancer clinical trials, some in Phase III. Inhibitory mechanisms within the tumor microenvironment (TME) represent major barriers to effective anti-tumor immunity. Although striking efficacy has been reported with inhibitory receptor (IR) blockade, it’s clear that additional inhibitory mechanisms will need to be targeted to substantially improve therapeutic outcome in most tumor types and for most patients. Regulatory T cells (Tregs) are potent inhibitors of anti-tumor immunity. Although Treg ablation results in rapid tumor shrinkage in multiple cancer models, this is not a viable therapeutic approach due to the subsequent severe autoimmune consequences. Thus, novel approaches are needed to limit Treg activity selectively in tumors, combined with a detailed understanding of their mechanism of action. We have previously focused on two main lines of inquiry, with emphasis on mechanisms that are selectively upregulated and impactful within the TME: [a] How do Tregs work in the TME? This led to the discovery of the inhibitory cytokine interleukin-35 (IL-35). [b] What potentiates Treg stability, survival and function? This led to the discovery of the NRP1:SEMA4A axis that controls Treg stability and function, and protects them from the negative impact of IFNg. Despite these seminal advances and their translation into the clinic, there is a substantive sense that many aspects of Treg function, stability, control and fate in the TME remain unknown. In the next seven years, my program will focus on two major questions: (1) Are there other cytokines or suppressive mechanisms used by Tregs in the TME? Discovery, mechanistic dissection and translation of novel Treg-derived cytokines within the TME, with emphasis on novel EBI3-containing heterodimers. (2) Are there other mechanisms that impact Treg stability, function & survival in the TME? Identification and dissection of novel mechanisms that control Treg stability and function in the TME, and/or impact their capacity to modulate cell types in the TME. This program will have a significant impact on our understanding of how Tregs manipulate and control the TME, will provide novel targets and modalities for therapeutic intervention in cancer, and will hopefully inspire others to develop novel approaches to target Tregs in cancer and other diseases.

项目摘要 我一直在剖析免疫调节的机制已有27年了，并且一直在发现和发现 剖析癌症中的免疫抑制机制超过10年。癌症免疫学和免疫疗法 现在占据了我的研究和翻译重点的80％。这不仅导致了许多以癌症为中心的 高影响力论文（11;自然[1]，细胞[1]，自然免疫学[4]，免疫[3]，科学免疫学[1]； 癌症研究[1]），自2016年以来为5，但也准备了免疫治疗药的发展 在多个癌症临床试验中靶向LAG3，EBI3和NRP1，其中一些在第三阶段中。 肿瘤微环境（TME）内的抑制性机制代表有效抗肿瘤的主要障碍 免疫。尽管已经据报道了抑制性接收器（IR）封锁的惊人效率，但很明显 在大多数情况下 肿瘤类型和大多数患者。调节性T细胞（Treg）是抗肿瘤免疫力的潜在抑制剂。虽然 Treg消融导致多种癌症模型中的肿瘤快速收缩，这不是一种可行的治疗方法 由于随后的严重自身免疫后果。那是需要新颖的方法来限制Treg 在肿瘤中有选择的活动，结合对其作用机理的详细理解。 我们以前已经专注于两个主要询问线，重点是选择性的机制 TME中的上调和影响力：[a] Tregs如何在TME中工作？这导致发现 抑制性细胞因子白介素35（IL-35）。 [b] Treg稳定性，生存和功能有什么潜力？这导致了 发现控制Treg稳定性和功能的NRP1：SEMA4A轴，并保护它们免受负面影响 IFNG的影响。尽管这些第二步及其转化为诊所，但仍有实质性的意义 TME中Treg功能，稳定性，控制和命运的许多方面仍然未知。 在接下来的七年中，我的计划将重点关注两个主要问题：（1）其他细胞因子或 TREG在TME中使用的抑制作用机制？发现，机械解剖和翻译 TME内的新型Treg衍生的细胞因子，重点是新型含EBI3的异二聚体。 （2）是 还有其他影响TME中Treg稳定性，功能和生存的机制？识别和 对控制TME中Treg稳定性和功能的新型机制的解剖和/或影响其容量 调节TME中的细胞类型。 该计划将对我们对Tregs如何操纵和控制TME的理解有重大影响， 将为癌症的热干预提供新颖的目标和方式，并有望激发他人 开发针对癌症和其他疾病中Treg的新方法。