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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.

项目总结/文摘