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

摘要：癌细胞的代谢变化对疾病的发展和发展具有深远的影响 进步。近年来，人们对脂肪酸β氧化的潜在作用越来越感兴趣 (粮农组织)在肿瘤发生中的作用。虽然多项研究表明，粮农组织对生物能量支持至关重要 关于癌细胞的生长，有新的证据表明粮农组织可能参与免疫调节。 然而，这一代谢途径在肿瘤免疫治疗诱导的抗肿瘤免疫中的确切作用 在很大程度上仍不为人所知。拟议的研究试图了解粮农组织的代谢过程， 以其速率设定酶肉碱棕榈酰基转移酶1A(CPT1A)为中心，是 肿瘤引起的免疫功能障碍阻碍了癌症的免疫治疗。我们的初步观察 提示粮农组织的异常升高损害了树突状细胞(DC)的功能，而DC在 启动和维持T细胞介导的抗肿瘤免疫。令人惊讶的是，选择性消融CPT1a在 DCs显著提高了对已建立的、免疫原性较差的肿瘤的免疫治疗效力。在这 应用，我们将使用独特的遗传工具和分子/免疫学方法来检验这一假说 CPT1a依赖的FAO通路定义了肿瘤相关DC的耐受性表型，并 促进肿瘤微环境中的免疫抑制(如PD-L1/2)。我们将确定 DC固有的粮农组织关于癌症免疫疗法，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- 作为衍生样本，我们将确定支持粮农组织受损的抗原提呈功能的机制 树突状细胞对免疫刺激药物的反应。我们还将首次将这一代谢途径联系起来 在功能上与炎症信号的负反馈调节有关，它可以决定免疫原性 树突状细胞和免疫耐受。此外，我们将研究粮农组织在癌细胞中的升高作为一种新的 他们对CTL治疗耐药的决定因素。最后，使用粮农组织已经批准的阻断药物 非癌症疾病的治疗我们将测试代谢干预的概念粮农组织的途径 重振免疫功能，并使癌细胞对CTL敏感。这个项目的成功完成是 预计将阐明一种先前未知的免疫抑制机制，涉及过度活跃的粮农组织 这提高了荷瘤宿主的免疫耐受性。对这一代谢途径的新见解 在癌细胞和肿瘤相关树突状细胞中的运作将促进我们对次优 大多数接受癌症免疫治疗的患者的反应。我们的发现可能会开启一种完全 通过重新编程异常的脂类分解代谢来重振癌症免疫疗法的新途径 对癌症的免疫防御。

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.