Metabolic reprograming of fatty acid beta-oxidation to improve cancer immunotherapy

脂肪酸β-氧化代谢重编程以改善癌症免疫治疗

• 批准号: 10361537
• 负责人: XIANJUN FANG
• 金额: $ 40.63万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10361537
• 关键词: Ablation; Acetyl Coenzyme A; Address; Antigen-Presenting Cells; Antigens; Attention; Biochemical; Bioenergetics; Biological Response Modifiers; Cancer Cell Growth; Cancer Patient; Carnitine; Carnitine Palmitoyltransferase I; Catabolism; Cell Lineage; Cell Therapy; Cell physiology; Cells; Citric Acid Cycle; Clinical; Correlative Study; Cytotoxic T-Lymphocytes; Data; Dendritic Cells; Development; Disease; Electron Transport; Environment; Enzymes; Fatty Acids; Feedback; Genetic; Glycolysis; Hyperactivity; Immune; Immune System Diseases; Immune Tolerance; Immune checkpoint inhibitor; Immunity; Immunization; Immunologics; Immunosuppression; Immunotherapeutic agent; Immunotherapy; Impairment; Inflammatory; Intervention; Link; Lipids; Lipoma; Lymphocyte Activation; Maintenance; Malignant Neoplasms; Malignant neoplasm of ovary; Mediating; Metabolic; Metabolic Pathway; Metabolism; Mitochondria; Modality; Modeling; Molecular; Mus; Outcome; Oxides; Pathway interactions; Patients; Pattern; Pharmaceutical Preparations; Pharmacology; Phase; Phenotype; Predisposition; Process; Protocols documentation; Research; Resistance; Role; Shapes; Signal Transduction; Site; Specimen; T-Lymphocyte; Testing; Time; Transportation; Tumor Escape; Tumor Immunity; Ubiquitin; Vaccine Therapy; Vaccines; anti-tumor immune response; cancer cell; cancer immunotherapy; cell killing; cell type; clinical translation; cytotoxicity; exhaustion; immune checkpoint; immune function; immunogenic; immunogenicity; immunoregulation; improved; inhibitor; innovation; insight; interest; long chain fatty acid; melanoma; mouse model; novel; oxidation; pre-clinical; programmed cell death ligand 1; response; success; targeted treatment; therapy resistant; tool; translational potential; tumor; tumor microenvironment; tumor progression; tumorigenesis

Summary: Metabolic alterations in cancer cells have profound effects in disease development and progression. In recent years, there has been increasing interest in potential roles of fatty acid β-oxidation (FAO) in tumorigenesis. While several studies have demonstrated that FAO is crucial for bioenergetic support of cancer cell growth, there is emerging evidence for potential involvement of FAO in immune modulation. However, the exact role of this metabolic pathway in antitumor immunity induced by cancer immunotherapy remains largely unknown. The proposed research seeks to understand the metabolic process of FAO, centered on its rate-setting enzyme carnitine palmitoyltransferase 1A (CPT1A), as a key contributing factor to tumor-induced immune dysfunction that impedes cancer immunotherapy. Our preliminary observations suggest that abnormal elevation in FAO impairs the function of dendritic cells (DCs), which are crucial for initiation and maintenance of T cell-mediated antitumor immunity. Strikingly, selective ablation of CPT1A in DCs markedly improves immunotherapeutic potency against established, poorly immunogenic tumors. In this application, we will use unique genetic tools and molecular/immunological approaches to test the hypothesis that the CPT1A-depedent FAO pathway defines a tolerogenic phenotype of tumor-associated DCs and promotes immune suppression (e.g., PD-L1/2) in the tumor microenvironment. We will determine the impact of DC-intrinsic FAO on cancer immunotherapies, including vaccines or immune checkpoint inhibitors, as well as mobilization of antigen-specific cytotoxic T lymphocytes (CTLs). Using preclinical mouse models and patient- derived specimens, we will define the mechanisms underpinning the FAO-impaired antigen-presenting function of DCs in response to immunostimulatory agents. We will also, for the first time, link this metabolic pathway functionally to a negative feedback regulator of inflammatory signaling, which can dictate the immunogenicity of DCs and immune tolerance. Moreover, we will investigate the elevation of FAO in cancer cells as a novel determinant of their therapeutic resistance to CTLs. Lastly, using the FAO-blocking drugs already approved for treatment of non-cancerous diseases we will test the concept of metabolic intervention of the FAO pathway to revitalize immune functions and to sensitize cancer cells to CTLs. Successful completion of this project is expected to elucidate a previously unrecognized immunosuppressive mechanism involving hyperactive FAO that promotes immune tolerance in the tumor-bearing host. New insights into this metabolic pathway that operates in both cancer cells and tumor-associated DCs will advance our understanding of a sub-optimal response in the majority of patients undergoing cancer immunotherapies. Our finding may open up an entirely new avenue for improved cancer immunotherapies by reprograming abnormal lipid catabolism to reinvigorate immune defense against cancer.

概述：癌细胞中的代谢改变对疾病的发展有深远的影响， 进展近年来，脂肪酸β-氧化的潜在作用引起了越来越多的关注 (FAO)在肿瘤发生中。虽然有几项研究表明，粮农组织对生物能源支持至关重要， 尽管粮农组织在癌症细胞生长方面发挥了重要作用，但有新的证据表明粮农组织可能参与免疫调节。 然而，这种代谢途径在癌症免疫治疗诱导的抗肿瘤免疫中的确切作用， 仍然是未知的。拟议的研究旨在了解粮农组织的代谢过程， 集中在其速率设定酶肉毒碱棕榈酰转移酶1A（CPT 1A），作为一个关键的促成因素， 肿瘤诱导的免疫功能障碍，阻碍癌症免疫治疗。我们的初步观察 这表明FAO的异常升高损害了树突状细胞（DC）的功能，而树突状细胞对于 启动和维持T细胞介导的抗肿瘤免疫。引人注目的是，选择性消融CPT 1A， DC显著提高了针对已建立的免疫原性差的肿瘤的免疫效力。在这 应用，我们将使用独特的遗传工具和分子/免疫学方法来测试假设 CPT 1A依赖性FAO途径定义了肿瘤相关DC的致耐受性表型， 促进免疫抑制（例如，PD-L1/2）在肿瘤微环境中的作用。我们将确定 DC-内在粮农组织对癌症免疫疗法，包括疫苗或免疫检查点抑制剂，以及 抗原特异性细胞毒性T淋巴细胞（CTL）的动员。使用临床前小鼠模型和患者- 衍生的标本，我们将定义FAO受损的抗原呈递功能的机制 DC对免疫刺激剂的反应。我们还将首次将这一代谢途径 在功能上与炎性信号传导的负反馈调节剂相关，这可以决定免疫原性 与免疫耐受的关系。此外，我们还将研究癌细胞中FAO的升高，作为一种新的研究方法。 它们对CTL的治疗抗性的决定因素。最后，使用粮农组织已经批准的阻断药物， 我们将测试粮农组织途径的代谢干预概念， 恢复免疫功能并使癌细胞对CTL敏感。该项目的成功完成是 有望阐明一种以前未被认识到的免疫抑制机制， 促进肿瘤宿主的免疫耐受。对这种代谢途径的新见解， 在癌细胞和肿瘤相关DC中起作用，将促进我们对次优 在大多数接受癌症免疫治疗的患者中，我们的发现可能会开启 通过重新编程异常脂质催化剂以重振癌症免疫治疗的新途径 对癌症的免疫防御。