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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/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，已然而，这些免疫疗法迄今为止在某些类型的癌症患者中取得了有希望的结果。显然，肿瘤反应性 T 细胞受到抑制并不足以可重复地消除肿瘤。抑制性肿瘤微环境功能失调，这是肿瘤成功的主要障碍因此，剖析导致 T 细胞功能障碍状态的不同机制。抑制性肿瘤微环境应该为肿瘤免疫治疗提供新的途径。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，也是一种新的机制。人类天然存在的调节性 T (Treg) 细胞和肿瘤来源的调节性 T (Treg) 细胞均利用抑制机制事实上，在肿瘤微环境中也发现了衰老CD8+ T细胞的大量积累。重要的是，我们发现这些在来自各种类型癌症患者的肿瘤浸润 T 细胞 (TIL) 中。衰老的 T 细胞具有功能抑制性，并且在分子上与无能和衰竭的 T 细胞不同并且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被 Treg 细胞抑制的应答 T 细胞对于制定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。我们最近发现 Treg 诱导的不同 T 细胞亚群具有不同的代谢特征。衰老的T细胞表现出活跃的脂质代谢，导致脂质代谢酶的上调和该提案的中心假设是分泌脂质种类和脂滴（LD）的积累。认为： 1）过度的脂质代谢对于效应器的衰老发育和免疫抑制至关重要 2）衰老和功能失调的肿瘤特异性T细胞可以通过以下方式恢复活力：脂质重编程增强抗肿瘤免疫力的具体目标 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具体目标 2 将探索新概念并制定有效策略来克服衰老。通过脂质代谢重编程结合选择性检查点来耗尽肿瘤特异性 T 细胞抗 PDL1 阻断疗法可增强过继性 T 细胞转移治疗肿瘤的抗肿瘤效率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。以及用于癌症治疗的肿瘤特异性 T 细胞的效应功能。