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

基本信息

批准号：
10599149
负责人：
XIANJUN FANG
金额：
$ 40.49万
依托单位：
VIRGINIA COMMONWEALTH UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10599149
关键词：
Ablation Acetyl Coenzyme A Address Antigen Presentation 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 Immunologic Stimulation 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 Pathway interactions Patients Pattern Pharmaceutical Preparations Phase Phenotype Predisposition Process Proliferating 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 carcinogenesis cell killing cell type clinical translation cytotoxicity exhaustion immune checkpoint immune function immune stimulatory agent immunogenic immunogenicity immunoregulation improved inhibitor innovation insight interest long chain fatty acid melanoma mouse model novel oxidation pharmacologic pre-clinical programmed cell death ligand 1 response success targeted treatment therapy resistant tool translational potential tumor tumor eradication tumor microenvironment tumor progression tumorigenesis

项目摘要

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.

摘要：癌细胞的代谢改变对疾病的发展具有深远的影响，进展。近年来，人们对脂肪酸β-氧化的潜在作用的兴趣越来越高。（粮农组织）在肿瘤发生中。虽然几项研究表明粮农组织对于生物能支持至关重要在癌细胞生长中，有新兴的证据表明粮农组织可能参与免疫调节。但是，该代谢途径在抗肿瘤免疫疗法中的确切作用仍然是未知的。拟议的研究试图了解粮农组织的代谢过程，以其速率定位酶肉碱棕榈酮Yltransferase 1A（CPT1A）为中心，作为关键因素的关键因素肿瘤诱导的免疫功能障碍会阻碍癌症免疫疗法。我们的初步观察表明FAO中异常升高会损害树突状细胞（DC）的功能，这对于至关重要 T细胞介导的抗肿瘤免疫史的起始和维持。令人惊讶的是，CPT1A的选择性消融 DC显着提高了针对已建立的免疫原性肿瘤的免疫治疗效力。在这个应用，我们将使用独特的遗传工具和分子/免疫方法来检验假设 CPT1A依赖的粮农组织途径定义了与肿瘤相关的DC的耐受性表型和在肿瘤微环境中促进免疫抑制（例如PD-L1/2）。我们将确定 DC Intrinsic粮农组织在癌症免疫疗法上，包括疫苗或免疫抑制剂，以及动员抗原特异性细胞毒性T淋巴细胞（CTLS）。使用临床前小鼠模型和患者 - 派生的标本，我们将定义基于粮农组织抗原呈现功能的机制 DC响应免疫刺激剂。我们还将第一次链接此代谢途径在功能上对炎症信号传导的负反馈调节剂，这可以决定免疫原性 DC和免疫耐受性。此外，我们将研究癌细胞中粮农组织的升高决定其对CTL的治疗性的决定因素。最后，使用已经批准的fao阻断药物治疗非癌性疾病，我们将测试粮农组织途径代谢干预的概念振兴免疫功能并感知到CTL的癌细胞。成功完成该项目的是有望阐明先前未知的免疫抑制机制这促进了肿瘤宿主中的免疫耐受性。对这种代谢途径的新见解在癌细胞和与肿瘤相关的DC中均可促进我们对亚地区的理解大多数接受癌症免疫疗法的患者的反应。我们的发现可能完全打开通过重新编程异常脂质分解代谢来振兴，改善癌症免疫疗法的新途径免疫防御癌症。