Targeting T Cell Senescence and Dysfunction for Anti-tumor Immunity

针对 T 细胞衰老和功能障碍的抗肿瘤免疫

• 批准号: 9981183
• 负责人: Guangyong Peng
• 金额: $ 34.66万
• 依托单位: SAINT LOUIS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9981183
• 关键词: ATM Signaling Pathway; Address; Adoptive Transfer; Affect; CTLA4 gene; Cancer Patient; Cell Aging; Cells; Clinical Trials; DNA Damage; Development; Disease; Enzymes; Exhibits; Functional disorder; Gene Expression Regulation; Generations; Human; Immune; Immune System Diseases; Immunosuppression; Immunotherapy; Inflammatory; Interruption; Investigation; Lead; Lipids; MAP Kinase Gene; MAPK3 gene; Malignant Neoplasms; Mediating; Metabolism; Modeling; Molecular; Mus; Outcome Study; PD-1/PD-L1; Pathway interactions; Phosphorylation; Process; Public Health; Regulatory T-Lymphocyte; Rejuvenation; Research; STAT1 gene; STAT3 gene; Signal Transduction; T-Lymphocyte; TLR8 gene; Testing; Therapeutic; Tumor Immunity; Tumor-Derived; anti-tumor immune response; cancer immunotherapy; cancer therapy; cancer type; cytokine; effector T cell; exhaust; glucose metabolism; immune checkpoint blockade; improved; lipid metabolism; melanoma; metabolic profile; neoplasm immunotherapy; neoplastic cell; novel; novel strategies; prevent; programs; response; senescence; sensor; success; targeted treatment; transcription factor; tumor

PROJECT SUMMARY/ABSTRACT Current immunotherapy strategies, including immune checkpoint blockade therapy targeting CTLA-4 and/or PD1/PD-L1, have yielded promising results in certain types of cancer patients. However, the overall success rates of these strategies still vary from 15% to 35%, which suggests that there are other mechanisms and/or checkpoint signaling involved that are unresponsive to therapy mediated by malignant tumors. Thus, alternative novel strategies targeting more specific checkpoint molecules or interrupting tolerogenic pathways are urgently needed. It is now well recognized that the suppression and dysfunction of tumor-reactive T cells induced by regulatory T cells (Treg) in the tumor suppressive microenvironment present a major barrier for successful anti-tumor immunotherapy. We recently discovered a novel suppressive mechanism whereby human Treg cells induce senescence in effector T cells that then exhibit potent suppressive activity and amplify immune suppression. Therefore, a better understanding of the cellular and molecular processes that control Treg-induced senescence in effector T cells is essential for the development of effective strategies to treat human cancer. We identified significantly increased activation of the energy sensor AMPK and dys- regulation of lipid metabolism in Treg-induced senescent T cells. Furthermore, ATM-associated DNA damage response and MAPK signaling were selectively involved in T cell senescence mediated by human Treg cells. In addition, we have discovered that human Toll-like receptor 8 (TLR8) signaling reverses the suppressive function and prevents the induction of T cell senescence mediated by both naturally occurring Treg and tumor- derived Treg cells. The central hypotheses of this proposal are that: 1) Human Treg cells can selectively modulate molecular programs that rewrite T cell lipid metabolism in treated naïve/effector T cells, resulting in their differentiation into senescent T cells; 2) Senescent and dysfunctional tumor-specific T cells can be rejuvenated via checkpoint blockages of ATM and MAPK signaling in responder T cells, combined with TLR8 signaling activation in Treg cells, resulting in enhanced anti-tumor immune responses. Specific Aim 1 seeks to identify the molecular mechanism(s) responsible for the induction of senescence and dysfunction in responder T cells after interaction with Treg cells. We will dissect how Treg cells molecularly rewrite effector T cell fate and lipid metabolism. Aim 2 will test the novel concept and strategy that TLR8-mediated reprogramming of glucose metabolism in Treg cells combined with checkpoint blockage of selective MAPK and/or ATM- associated DNA damage signaling in responder T cells can synergistically enhance anti-tumor immunity through reversing the senescence and dysfunction of tumor-specific T cells. A positive outcome of these studies should lead to novel strategies to reprogram Treg metabolism and control the fate and function of tumor-specific T cells for the treatment of human cancers.

项目摘要/摘要 当前的免疫疗法策略，包括针对CTLA-4和/或的免疫障碍障碍疗法 PD1/PD-L1在某些类型的癌症患者中产生了希望。但是，总体成功 这些策略的比率仍然从15％到35％不等，这表明还有其他机制和/或 检查点信号传导对由恶性肿瘤介导的治疗无反应。那， 针对更具体的检查点分子或中断耐受性途径的替代新型策略 迫切需要。现在众所周知，肿瘤反应性T细胞的抑制和功能障碍 肿瘤抑制微环境中由调节性T细胞（TREG）诱导的主要障碍 成功的抗肿瘤免疫疗法。我们最近发现了一种新颖的抑制作用机制 人treg细胞在效应T细胞中诱导感应，然后暴露了有效的抑制活性， 放大免疫抑制。因此，更好地了解细胞和分子过程 控制Treg诱导的效应T细胞中的感受对于制定有效策略至关重要 治疗人类癌。我们确定能量传感器AMPK和DYS的激活显着增加 调节Treg诱导的感觉T细胞中脂质代谢。此外，与ATM相关的DNA损伤 反应和MAPK信号传导选择性地参与了由人treg细胞介导的T细胞感应。 此外，我们发现人Toll样受体8（TLR8）信号传导逆转抑制 功能并防止天然发生的Treg和肿瘤介导的T细胞感受的诱导 衍生的Treg细胞。该提议的中心假设是：1）人treg细胞可以选择性地 调节在处理过的幼稚/效应T细胞中重写T细胞脂质代谢的分子程序，从而导致 它们分化为感觉T细胞； 2）衰老和功能失调的肿瘤特异性T细胞可以是 通过ATM和MAPK信号在响应者T细胞中的ATM和MAPK信号传导的检查点的恢复活力，与TLR8结合 Treg细胞中的信号传导激活，从而增强了抗肿瘤免疫反应。特定目标1试图 确定负责诱导响应者感应和功能障碍的分子机制 与Treg细胞相互作用后T细胞。我们将剖析Treg细胞分子如何重写效应T细胞命运 和脂质代谢。 AIM 2将测试TLR8介导的重新编程的新颖概念和策略 Treg细胞中的葡萄糖代谢与选择性MAPK和/或ATM-的检查点阻塞结合 响应者T细胞中相关的DNA损伤信号传导可以协同增强抗肿瘤免疫史地 通过逆转肿瘤特异性T细胞的感受和功能障碍。这些的积极结果 研究应导致新的策略重新编程Treg代谢并控制命运和功能 用于治疗人类癌症的肿瘤特异性T细胞。