Regulation of gamma delta T cell immunoediting by novel phosphoantigens

新型磷酸抗原对 γδT 细胞免疫编辑的调节

• 批准号: 9215652
• 负责人: ANDREW J WIEMER
• 金额: $ 37.78万
• 依托单位: UNIVERSITY OF CONNECTICUT STORRS
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9215652
• 关键词: Address; Adverse effects; Affect; Affinity; American; Antibodies; Antibody Therapy; Antigens; Bacteria; Binding; Biological; Cancerous; Cells; Chemicals; Clinical; Communicable Diseases; Cytolysis; Data; Development; Diphosphates; Disease; Dose; Drug Kinetics; Effectiveness; Employee Strikes; Exhibits; Goals; Growth; Human; Immune; Immune response; Immune system; Immunity; Immunotherapy; In Vitro; Infection; Inflammatory; Integrins; Intravenous; Libraries; Lymphoma; Lytic; Malignant Neoplasms; Mediating; Metabolic; Metabolism; Modeling; Molecular Target; Osteoporosis; Patients; Peptides; Permeability; Pharmaceutical Preparations; Phosphonic Acids; Phosphorus; Primates; Production; Public Health; Receptor Cell; Regulation; Research; Risedronate; Risk; Rodent; Series; Structure-Activity Relationship; Syndrome; T-Cell Receptor; T-Lymphocyte; TNF gene; Testing; Therapeutic; Therapeutic Index; Time; alpha-beta T-Cell Receptor; analog; base; bisphosphonate; bone; cancer cell; cancer immunotherapy; cancer risk; cancer therapy; chemical stability; compound 30; cytokine; fighting; humanized mouse; in vivo; isopentenyl pyrophosphate; kinase inhibitor; leukemia/lymphoma; mouse model; neoplastic cell; novel; phosphonate; public health relevance; receptor; response; small molecule; tool; trafficking; tumor; uptake; γδ T cells

 DESCRIPTION (provided by applicant): An attractive strategy for cancer treatment is to strengthen the ability of the patient's own immune system to detect and clear cancerous cells. However, current antibody-based or cell-based immunotherapies have limited effectiveness or high invasiveness. A small molecule drug that activates the immune system to fight cancer would be an attractive clinical option because it may not require the intravenous dosing associated with antibody therapies and it would be less invasive than cell based options. The objective of our research is to develop a drug that stimulates the immune response to cancer by activating cells known as the gamma delta T cells. Gamma delta T cells are early responders to malignancy, and as such, their activation holds great promise for cancer immunotherapy. In contrast to T cells that express the more prevalent alpha beta T cell receptor and respond to peptide antigens, T cells that express the V9V2 T cell receptor respond to small phosphorous-containing compounds known as phosphoantigens. As a side effect of treatment for osteoporosis, nitrogenous bisphosphonate drugs indirectly activate gamma delta T cells by enhancing accumulation of the phosphoantigen isopentenyl diphosphate, substantially reducing the risk of some cancers. However, no known direct activators of gamma delta T cells are available for human use. Here, we propose to test the central hypothesis that phosphonate phosphoantigens with enhanced metabolic stability will directly activate gamma delta T cells, in a way that is dependent upon cellular internalization and integrin- mediated cell contact. Development of a new class of phosphoantigens is essential because clinical use of bisphosphonate drugs to activate gamma delta T cells is limited by their narrow therapeutic index and high bone affinity, and clinical use of natural phosphoantigens is limited due to rapid diphosphate metabolism. We will synthesize a series of novel organophosphorous compounds with increased metabolic stability relative to known phosphoantigens and characterize their activation of gamma delta T cells. We also will prepare protected phosphoantigens, which will allow us to continue to investigate how enhanced cellular uptake promotes a stronger response. We will use these new chemical tools to address the fundamental unanswered question of how phosphoantigens activate gamma delta T cells to fight cancer. The ultimate goal is to identify a phosphoantigen that will be used for cancer treatment. These findings will come at a time when the biological understanding of anti- cancer immunity is far from complete, and thus have the potential for dramatic impact on the field of cancer immunotherapy.

 描述（由适用提供）：癌症治疗的一种有吸引力的策略是增强患者自身的免疫疗法系统检测和清除癌细胞的能力。但是，当前基于抗体或基于细胞的免疫疗法的有效性有限或侵入性高。一种激活免疫系统来抗癌的小分子药物将是一种有吸引力的临床选择，因为它可能不需要与抗体疗法相关的静脉注射剂量，并且它比基于细胞的剂量的侵入性较小。我们研究的目的是开发一种药物，该药物通过激活称为伽马三角细胞的细胞来刺激对癌症的免疫响应。伽马三角细胞是对恶性肿瘤的早期反应者，因此，它们的激活对癌症免疫疗法具有很大的希望。与表达更为普遍的αβT细胞接收器并对胡椒抗原反应的T细胞相反，表达V9V2T细胞接收器的T细胞对含磷酸化的小化合物的反应反应称为磷脂剂。作为治疗骨质疏松症的副作用，氮双膦酸盐药物通过增强磷酸剂异戊烯基二磷酸的加速度间接激活γ三角细胞，从而大大降低了某些取消者的风险。但是，没有已知的伽马三角中T细胞的直接激活剂可供人类使用。在这里，我们建议测试中心假设，即具有增强的代谢稳定性的磷酸剂将直接激活伽马三角细胞，这种方式取决于细胞内在化和整合介导的细胞接触。一类新的磷酸剂的开发是必不可少的，因为双膦酸盐药物激活伽马三角细胞的临床使用受其狭窄的治疗指数和高骨亲和力的限制，并且由于快速的二磷酸代谢而快速的天然磷抗菌剂的临床使用受到限制。我们将合成一系列新型有机化合物，相对于已知的磷酸剂，其代谢稳定性增加，并表征它们激活伽马三角细胞。我们还将准备受保护的磷酸剂，这将使我们能够继续研究增强的细胞摄取如何促进更强的反应。我们将使用这些新的化学工具来解决磷酸剂如何激活伽马三角细胞以对抗癌症的基本未解决的问题。最终目标是确定将用于癌症治疗的磷酸剂。这些发现将是在对抗癌免疫史的生物学理解远非完整的，因此具有对癌症免疫疗法领域产生巨大影响的潜力。