Excessive lipid metabolism in T cell senescence and immunosuppression

T细胞衰老和免疫抑制中的过度脂质代谢

• 批准号: 10735675
• 负责人: Guangyong Peng
• 金额: $ 38.88万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-03 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10735675
• 关键词: Address; Affect; Amplifiers; Breast Melanoma; CD8-Positive T-Lymphocytes; Cancer Patient; Cell Aging; Cell Survival; Cell Therapy; DNA Damage; Development; Disease; Energy Metabolism; Enzymes; Exhibits; Functional disorder; Generations; Human; Immune System Diseases; Immune response; Immunosuppression; Immunotherapy; Lipids; Malignant Neoplasms; Mediating; Mediator; Metabolic; Metabolic Diseases; Metabolism; Modeling; Molecular; Outcome Study; PD-L1 blockade; Phenotype; Process; Proliferating; Public Health; Regulatory T-Lymphocyte; Rejuvenation; Reproducibility; Research; Role; T cell therapy; T-Cell Development; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Treatment Efficacy; Tumor Immunity; Tumor Suppression; Tumor-Derived; Up-Regulation; Writing; anti-PD-L1; anti-PD-L1 therapy; cancer infiltrating T cells; cancer therapy; cancer type; cytokine; effector T cell; exhaust; exhaustion; experimental study; immune checkpoint; immune checkpoint blockade; improved; in vivo; lipid metabolism; malignant breast neoplasm; metabolic profile; mitochondrial dysfunction; neoplasm immunotherapy; novel; novel strategies; prevent; programs; senescence; tumor; tumor microenvironment

PROJECT SUMMARY/ABSTRACT Current immunotherapies, including immune checkpoint blockage therapy and adoptive T cell therapy, have resulted in promising results in certain types of cancer patients. However, these immunotherapies have so far been insufficient to reproducibly eliminate tumors. It is clear that tumor-reactive T cells are suppressed and dysfunctional in the suppressive tumor microenvironment that is a major obstacle for successful tumor immunotherapy. Thus, dissecting the distinct mechanisms responsible for T cell dysfunctional states within the suppressive tumor microenvironment should provide novel avenues for tumor immunotherapy. We discovered that induction of T cell senescence is an important T cell dysfunctional state and a novel suppressive mechanism utilized by both human naturally occurring and tumor-derived regulatory T (Treg) cells in the tumor microenvironment. In fact, significant accumulation of senescent CD8+ T cells has also been found in the tumor-infiltrating T cells (TILs) from various types of cancer patients. Importantly, we found that these senescent T cells are functionally suppressive and molecularly distinct from anergic and exhausted T cellsand that they are a critical mediator and amplifier for immune suppression within the tumor microenvironments. Therefore, a better understanding of this novel suppressive mechanism and the molecular processes in responder T cells suppressed by Treg cells is essential for the development of effective strategies to treat human cancers. Cellular energy metabolism directs T cell survival, proliferation and their specific functions. Different T cell subsets have different metabolic profiles. We have more recently identified that Treg-induced senescent T cells exhibit active lipid metabolism, resulting in upregulation of lipid metabolic enzymes and secretory lipid species, and accumulation of lipid droplets (LDs). The central hypotheses of this proposal are that: 1) Excessive lipid metabolism is critical for senescence development and immunosuppression of effector T cells mediated by Treg cells; 2) Senescent and dysfunctional tumor-specific T cells can be rejuvenated via lipid reprogramming for enhanced anti-tumor immunity. Specific Aim 1 seeks to identify whether the excessive lipid metabolism is involved in senescence development and immunosuppression of T cells induced by Treg cells. Specific Aim 2 will explore the novel concept and develop effective strategies to overcome senescent and exhausted tumor-specific T cells via lipid metabolism reprogramming combined with selective checkpoint blockage therapy of anti-PDL1 for enhanced anti-tumor efficiency in the adoptive T cell transfer therapy tumor models. The positive outcome of these studies should lead to novel strategies to reprogram lipid metabolism and effector functions of tumor-specific T cells for cancer treatments.

项目总结/摘要 目前的免疫疗法，包括免疫检查点阻断疗法和过继性T细胞疗法， 在某些类型的癌症患者身上取得了令人鼓舞的结果。然而，迄今为止，这些免疫疗法 不足以重复消除肿瘤。很明显，肿瘤反应性T细胞被抑制， 在抑制性肿瘤微环境中功能失调，这是成功肿瘤的主要障碍。 免疫疗法。因此，解剖T细胞功能障碍状态的不同机制， 抑制性肿瘤微环境为肿瘤免疫治疗提供了新途径。 我们发现诱导T细胞衰老是一种重要的T细胞功能障碍状态， 人天然存在的和肿瘤衍生的调节性T（Treg）细胞利用的抑制机制 在肿瘤微环境中。事实上，还发现了衰老的CD 8 + T细胞的显著积累。 肿瘤浸润性T细胞（TILs）中的免疫反应。重要的是，我们发现， 衰老的T细胞在功能上是抑制性的，并且在分子上不同于无反应性和衰竭的T细胞， 它们是肿瘤微环境中免疫抑制的关键介质和放大器。 因此，更好地了解这种新的抑制机制和分子过程， Treg细胞抑制的应答T细胞对于开发有效的治疗策略至关重要。 人类癌症细胞能量代谢指导T细胞的存活、增殖及其特定功能。 不同的T细胞亚群具有不同的代谢谱。我们最近发现Treg诱导的 衰老T细胞表现出活跃的脂质代谢，导致脂质代谢酶的上调， 分泌脂质种类和脂滴（LD）的积累。这一建议的主要假设是 认为：1）脂质代谢过度是衰老发展和效应细胞免疫抑制的关键 Treg细胞介导的T细胞; 2）衰老和功能失调的肿瘤特异性T细胞可以通过免疫调节剂来再生。 脂质重编程以增强抗肿瘤免疫力。具体目标1旨在确定是否过度 脂质代谢参与Treg诱导的T细胞衰老发育和免疫抑制 细胞具体目标2将探索新的概念，并制定有效的策略，以克服衰老 并通过脂质代谢重编程结合选择性检查点耗尽肿瘤特异性T细胞 用于增强过继性T细胞转移疗法肿瘤中的抗肿瘤效率的抗PDL 1阻断疗法 模型这些研究的积极结果应该会导致重新编程脂质代谢的新策略 和肿瘤特异性T细胞的效应子功能用于癌症治疗。