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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.

总结：癌细胞的代谢改变对疾病的发展和预后有深远的影响