Combination of ceramide and immunotherapy in treatment of hepatocellular cancer

神经酰胺与免疫疗法联合治疗肝细胞癌

• 批准号: 9403358
• 负责人: MARK KESTER
• 金额: $ 53.12万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9403358
• 关键词: Acyl Coenzyme A; Adoptive Transfer; Animal Model; Antibodies; Apoptosis; CD8-Positive T-Lymphocytes; Cancer Control; Cells; Cellular Morphology; Ceramides; Clinical; Clinical Trials; Data; Drug Delivery Systems; Endothelial Cells; Evaluation; Frequencies; Funding; Future; Generations; Growth; Hepatocyte; Human; Immune; Immune Evasion; Immune System Diseases; Immune System and Related Disorders; Immune Tolerance; Immune response; Immune system; Immunity; Immunization; Immunocompetent; Immunodeficient Mouse; Immunotherapeutic agent; Immunotherapy; Interferons; Intervention; Lead; Liver; Liver Fibrosis; Malignant Neoplasms; Mediating; Modeling; Molecular; Mus; Myelogenous; N-caproylsphingosine; Nanotechnology; Oncogenic; Oxidoreductase; PDCD1LG1 gene; Pathogenesis; Pathway interactions; Patients; Performance; Pharmaceutical Preparations; Phase; Phenotype; Precipitation; Prevention; Primary carcinoma of the liver cells; Property; Reactive Oxygen Species; Regulatory T-Lymphocyte; Safety; Second Messenger Systems; Seminal; Site; Small Business Innovation Research Grant; Solid Neoplasm; Sphingolipids; Suppressor-Effector T-Lymphocytes; Testing; Therapeutic; Therapeutic Effect; Transplantation; Treatment Efficacy; Tumor Antigens; Tumor Immunity; Tumor Suppression; United States National Institutes of Health; Up-Regulation; aqueous; base; cancer cell; cancer initiation; cancer therapy; cancer type; clinical translation; clinically relevant; efficacy testing; exhaust; exhaustion; innovation; insight; intrahepatic; macrophage; man; mouse model; nanoliposome; neoplastic cell; novel; preclinical safety; standard of care; therapeutic target; tumor; tumor growth; tumor progression

ABSTRACT Great progress has been made in manipulating the immune system to eliminate established tumors including hepatocellular cancer (HCC). However, the lack of a clinically-relevant animal model largely impedes our understanding of HCC-induced immune evasion. Therefore, prevention of tumor-induced immunotolerance to develop effective immunotherapies against HCC is still a challenging task. We recently created a novel murine model with immunocompetent mice. This model reflects most typical features of human HCC including immune escape. Tumor growth in this model induces profound immune tolerance characterized by increase in the frequency of tumor-associated macrophages (TAMs), regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs), liver sinusoidal endothelial cells (LSECs) as well as profound exhaustion of effector CD8+T cells. We have thus established a unique platform to investigate the mechanism of tumor-induced immune tolerance and to develop proof-of-concept therapeutic strategies for HCC toward eventual clinical translation. Ceramide has tumoricidal activity. We use advanced nanotechnology to make nanoliposome-loaded C6- ceremide (LipC6). The formulated LipC6 overcomes ceramide cell impermeability and aqueous precipitation, while enhancing cellular retention, promoting its clinical use as a drug. The combination of LipC6 with adoptive transfer of tumor antigen-specific CD8+ T-cell plus immunization with tumor-specific antigens not only retarded tumor growth but also regressed established tumors, suggesting that the combination of LipC6 with immunotherapies has a synergistic therapeutic effect in HCC control. The overall objective of this proposal is to dissect the underlying mechanisms by which LipC6 breaks tumor-induced immune tolerance to rescue antitumor immune activity and develop a clinically useful LipC6-integrated immunotherapy for HCC. Further studies reveal that LipC6 treatment modulates TAM and LSEC in cellular level; and regulates reactive oxygen species (ROS), interferon regulator factor (IRF), and fatty acyl-COA reductase 2(Far2), PD1 in molecular level in HCC. Anti-PD1 antibodies treatment effectively impedes HCC growth. Thus, we hypothesize that LipC6 targets TAM and LSEC to resurrect anti-tumor immune reactivity by regulating ROS, IRF, and Far2 pathways; thus LipC6 in combination with anti-PD1 antibodies to block PD1/PD-L1 pathway not only strongly activate anti-HCC immunity but also result in unprecedented therapeutic efficacy. We will test our hypothesis through aims 1: Dissect the cellular mechanisms by which LipC6 modulates TAM and LSEC to impact anti-tumor immunity in tumor-bearing mice. 2. Dissect the molecular mechanisms by which LipC6 modulates macrophages through ROS and IRF pathways, and LSEC through Far2 pathway in the setting of HCC. 3. Define the therapeutic efficacy of LipC6 in combination with anti-PD-1 Abs for HCC treatment and elucidate the underlying mechanisms. This study will provide better insights into the mechanisms of an effective LipC6-immunotherapeutic intervention in HCC control. The findings will lead to new treatments and therapeutic targets, and better anticancer strategies.

摘要 在操纵免疫系统消除已建立的肿瘤方面已经取得了很大的进展 包括肝细胞癌（HCC）。然而，缺乏临床相关的动物模型在很大程度上阻碍了 我们对肝癌诱导的免疫逃避的理解。因此，预防肿瘤诱导的免疫耐受 开发有效的抗HCC的免疫疗法仍然是一项具有挑战性的任务。我们最近创造了一种新的鼠 免疫活性小鼠模型。该模型反映了人类HCC的最典型特征，包括免疫学特征， 逃跑该模型中的肿瘤生长诱导了显著的免疫耐受性，其特征在于免疫耐受性增加。 肿瘤相关巨噬细胞（TAMs）、调节性T细胞（Treg）和骨髓源性抑制细胞的频率 细胞（MDSC）、肝窦内皮细胞（LSEC）以及效应CD 8 +T细胞的深度耗竭。 因此，我们建立了一个独特的平台，探讨肿瘤诱导免疫耐受的机制 并为HCC的最终临床转化开发概念验证治疗策略。 神经酰胺具有杀肿瘤活性。我们使用先进的纳米技术来制造纳米脂质体负载的C6- Ceremide（LipC6）。配制的LipC 6克服了神经酰胺细胞不透性和水沉淀， 同时增强细胞滞留，促进其作为药物的临床应用。LipC 6与过继性 肿瘤抗原特异性CD 8 + T细胞的转移加上肿瘤特异性抗原的免疫不仅延缓了 肿瘤生长，但也消退了建立的肿瘤，这表明LipC 6与 免疫疗法在HCC控制中具有协同治疗作用。本建议的总体目标是 剖析LipC 6打破肿瘤诱导的免疫耐受以拯救抗肿瘤药物的潜在机制。 免疫活性，并开发用于HCC的临床有用的LipC 6整合免疫疗法。 进一步的研究表明，LipC 6处理在细胞水平上调节TAM和LSEC;并调节 活性氧（ROS）、干扰素调节因子（IRF）和脂肪酰辅酶A还原酶2（Far 2）、PD 1 在分子水平上对HCC的影响。抗PD 1抗体治疗有效地阻止了HCC的生长。因此，我们假设 LipC 6靶向TAM和LSEC，通过调节ROS、IRF和Far 2来恢复抗肿瘤免疫反应性， 因此，LipC 6与抗PD 1抗体组合不仅强烈阻断PD 1/PD-L1途径， 激活抗HCC免疫，而且还产生前所未有的治疗功效。我们将测试我们的假设 通过目标1：剖析LipC 6调节TAM和LSEC以影响抗肿瘤的细胞机制 荷瘤小鼠的免疫力。2.剖析LipC 6调节巨噬细胞的分子机制 在HCC的情况下，LSEC通过ROS和IRF途径，LSEC通过Far 2途径。3.定义治疗 本发明的目的在于评估LipC 6与抗PD-1 Ab组合用于HCC治疗的功效并阐明潜在机制。 这项研究将为有效的LipC 6免疫干预机制提供更好的见解。 HCC控制。这些发现将导致新的治疗方法和治疗靶点，以及更好的抗癌策略。