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

基本信息

批准号：
10557127
负责人：
Guangyong Peng
金额：
$ 40.87万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
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/10557127
关键词：
ATM Signaling Pathway Address Adoptive Transfer Affect CTLA4 gene Cancer Patient Cell Aging Cell Senescence Induction Cells Cellular Metabolic Process Clinical Trials DNA Damage Development Disease Enzymes Exhibits Functional disorder Gene Expression Regulation Generations Human Immune Immune System Diseases Immunosuppression Immunotherapy Inflammatory Interruption Investigation 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 Reproducibility Research STAT1 gene STAT3 gene Signal Transduction T-Lymphocyte TLR8 gene Testing Therapeutic Tumor Immunity Tumor-Derived Writing 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 p38 Mitogen Activated Protein Kinase prevent programs response senescence sensor success targeted treatment transcription factor tumor

项目摘要

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.

项目概要/摘要当前的免疫治疗策略，包括针对 CTLA-4 的免疫检查点阻断治疗和/或 PD1/PD-L1 在某些类型的癌症患者中取得了有希望的结果，但总体上取得了成功。这些策略的比率仍然在 15% 到 35% 之间变化，这表明还有其他机制和/或涉及的检查点信号对恶性肿瘤介导的治疗无反应。针对更具体的检查点分子或中断耐受性途径的替代新策略现在人们普遍认识到肿瘤反应性T细胞的抑制和功能障碍。肿瘤抑制微环境中的调节性 T 细胞 (Treg) 诱导的肿瘤形成了主要障碍我们最近发现了一种成功的抗肿瘤免疫疗法。人类 Treg 细胞诱导效应 T 细胞衰老，然后表现出有效的抑制活性因此，更好地了解免疫抑制的细胞和分子过程。控制 Treg 诱导的效应 T 细胞衰老对于制定有效策略至关重要我们发现能量传感器 AMPK 的激活显着增加并且异常。 Treg 诱导的衰老 T 细胞中脂质代谢的调节此外，ATM 相关的 DNA 损伤。反应和 MAPK 信号选择性参与人类 Treg 细胞介导的 T 细胞衰老。此外，我们发现人类 Toll 样受体 8 (TLR8) 信号传导可逆转抑制功能并防止自然发生的 Treg 和肿瘤介导的 T 细胞衰老诱导该提案的中心假设是：1）人类Treg细胞可以选择性地产生。调节分子程序，重写经处理的初始/效应 T 细胞中的 T 细胞脂质代谢，从而导致 2）衰老和功能失调的肿瘤特异性T细胞可以通过应答 T 细胞中 ATM 和 MAPK 信号传导的检查点阻断，结合 TLR8 来恢复活力具体目标 1 旨在激活 Treg 细胞中的信号传导，从而增强抗肿瘤免疫反应。确定导致应答者衰老和功能障碍的分子机制 T 细胞与 Treg 细胞相互作用后，我们将剖析 Treg 细胞如何从分子角度改写效应 T 细胞的命运。目标 2 将测试 TLR8 介导的重编程的新概念和策略。 Treg 细胞中的葡萄糖代谢与选择性 MAPK 和/或 ATM-检查点阻断相结合应答 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力通过逆转肿瘤特异性 T 细胞的衰老和功能障碍，取得了积极的成果。研究应该会产生新的策略来重新编程 Treg 代谢并控制 Treg 的命运和功能用于治疗人类癌症的肿瘤特异性 T 细胞。