Regulatory T cells and the tumor microenvironment

项目摘要 我一直在解剖免疫调节机制约27年，并一直在发现和 研究癌症的免疫抑制机制超过10年。癌症免疫学和免疫治疗 现在占据了我80%的研究和翻译重点。这不仅导致了许多癌症集中在 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年以来有5个，但也促进了免疫治疗的发展 靶向LAG 3、EBI 3和NRP 1的多项癌症临床试验，其中一些处于III期。 肿瘤微环境（TME）内的抑制机制代表了有效抗肿瘤治疗的主要障碍。 免疫力尽管抑制性受体（IR）阻滞剂的疗效显著，但很明显， 在大多数情况下，需要靶向另外的抑制机制以显著改善治疗结果。 肿瘤类型和大多数患者。调节性T细胞（Regulatory T cells，Tcells）是抗肿瘤免疫的有效抑制剂。虽然 Treg消融导致多种癌症模型中的肿瘤快速缩小，这不是可行的治疗方法 因为随之而来的严重的自身免疫性后果因此，需要新的方法来限制Treg 活性选择性地在肿瘤中，结合其作用机制的详细了解。 我们以前着重于两条主要的调查路线，重点是有选择地 在TME中上调和有影响力：[a] TME如何在TME中发挥作用？这就导致了 抑制性细胞因子白细胞介素-35（IL-35）。[b]是什么增强了Treg的稳定性、存活率和功能？这导致 发现NRP 1：SEMA 4A轴，控制Treg稳定性和功能，并保护它们免受负作用。 IFNg的影响。尽管有这些开创性的进展，并将其转化为临床， TME中Treg功能、稳定性、控制和命运的许多方面仍然未知。 在接下来的七年里，我的计划将集中在两个主要问题上：（1）是否有其他细胞因子或 TME中使用的抑制机制？的发现、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EBI 3的异源二聚体。(2)是 是否有其他机制影响TME中Treg的稳定性、功能和存活？识别和 剖析控制TME中Treg稳定性和功能和/或影响其能力的新机制 来调节TME中的细胞类型。 该计划将对我们理解TME如何操纵和控制TME产生重大影响， 将为癌症的治疗干预提供新的靶点和模式，并有望启发其他人， 开发新的方法来靶向癌症和其他疾病中的TcR。

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.