Regulation of gamma delta T cell immunoediting by novel phosphoantigens

 描述（由申请人提供）：一种有吸引力的癌症治疗策略是增强患者自身免疫系统检测和清除癌细胞的能力。然而，目前基于抗体或基于细胞的免疫疗法具有有限的有效性或高侵袭性。激活免疫系统以对抗癌症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内给药，并且它比基于细胞的选择侵入性更小。我们研究的目的是开发一种药物，通过激活称为γ δ T细胞的细胞来刺激对癌症的免疫反应。γ δ T细胞是恶性肿瘤的早期反应者，因此，它们的激活为癌症免疫治疗带来了巨大的希望。与表达更普遍的α β T细胞受体并对肽抗原作出反应的T细胞相反，表达V β 9 V β 2 T细胞受体的T细胞对称为磷酸化抗原的小的含磷化合物作出反应。作为骨质疏松症治疗的副作用，含氮双膦酸盐药物通过增强磷酸化抗原异戊烯基二磷酸的积累间接激活γ δ T细胞，从而大大降低了某些癌症的风险。然而，没有已知的γ δ T细胞的直接活化剂可用于人类使用。在这里，我们提出测试中心假设，即具有增强的代谢稳定性的膦酸盐磷酸化抗原将以依赖于细胞内化和整合素介导的细胞接触的方式直接激活γ δ T细胞。开发一类新的磷酸化抗原是必要的，因为双膦酸盐药物激活γ δ T细胞的临床应用受到其狭窄的治疗指数和高骨亲和力的限制，并且天然磷酸化抗原的临床应用由于快速的二磷酸盐代谢而受到限制。我们将合成一系列新的有机磷化合物，相对于已知的磷酸化抗原具有更高的代谢稳定性，并表征其对γ δ T细胞的活化。我们还将制备受保护的磷酸化抗原，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化抗原如何激活γ δ T细胞以对抗癌症的基本未回答的问题。最终的目标是确定一个磷酸化抗原，将用于癌症治疗。这些发现将在抗癌免疫的生物学理解远未完成的时候出现，因此有可能对癌症免疫治疗领域产生巨大影响。

 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.