"Cancer Immunotherapy by Targeting A2 Adenosine Receptor"

描述(申请人提供)：据信癌症免疫治疗的应用是有限的，因为抗肿瘤T细胞在实体瘤的免疫抑制微环境中被抑制。这项提案的总体目标是通过灭活肿瘤附近或肿瘤内抑制抗肿瘤T细胞的机制，使癌症免疫治疗更加有效。这一建议的中心假设是，基因缺失或药物灭活免疫抑制，Gs蛋白偶联A2腺苷受体亚型A2A和A2B(分别为A2AR和A2BR)应防止抗肿瘤T细胞的抑制，从而促进其完全排斥反应。这一假说源于我们早先的发现，即A2AR和A2BR在保护正常组织(如肝脏和肺)免受急性炎症和缺氧区过度活跃的免疫细胞的影响方面发挥着关键作用。我们的初步结果证实了这一假说，证明了大肿瘤完全或显著改善的排斥反应 -60%的小鼠A2AR基因失活。我们的数据强烈表明，A2AR和A2BR都应该被灭活，以便在100%的小鼠中消除肿瘤保护。在这里，我们建议利用这一新的认识，通过使抗肿瘤T细胞抵抗肿瘤产生的腺苷的抑制来实现肿瘤的完全排斥。这将通过在小鼠中同时缺失A2AR和A2BR的基因来实现，或者通过用对A2AR和A2BR都有选择性的新型拮抗剂来治疗荷瘤小鼠，或者通过在体外扩增过程中否定选择“可抑制的”抗肿瘤T细胞来实现。这种独特类型的小鼠--A2AR或A2BR或两者都缺乏-将被用来测试这一改进癌症免疫治疗的新的可行策略。

DESCRIPTION (provided by applicant): It is believed that cancer immunotherapy applications are limited because anti-tumor T cells are inhibited in the immunosuppressive microenvironment of solid tumors. The overall goal of this proposal is to render cancer immunotherapies more effective by inactivating mechanisms that inhibit anti-tumor T cells near or within tumors. The central hypothesis of this proposal is that genetic deletion or pharmacological inactivation of immunosuppressive, Gs protein coupled A2 adenosine receptor subtypes A2A and A2B (A2AR and A2BR, respectively) should prevent the inhibition of anti-tumor T cells and thus facilitate their complete rejection. This hypothesis was prompted by our earlier findings that A2AR and A2BR play a critical role in the protection of normal tissues (e.g., liver and lung) from overactive immune cells in acutely inflamed and hypoxic areas. Our preliminary results confirmed this hypothesis by demonstrating the complete or much improved rejection of large tumors in approximately -60% mice with genetically inactivated A2AR. Our data strongly suggest that both A2AR and A2BR should be inactivated in order to eliminate tumor protection in 100% of mice. Here we propose to take advantage of this new understanding to accomplish the complete rejection of tumors by making anti-tumor T cells resistant to inhibition by tumor-produced adenosine. This will be done via genetic deletion of both A2AR and A2BR in mice, or by treatments of tumor-bearing mice with novel antagonists selective for both A2AR and A2BR or by negative selection of "inhibitable" anti-tumor T cells during expansion in vitro. Unique types of mice-deficient in A2AR or A2BR or both---will be used to test this novel and feasible strategy to improve the immunotherapy of cancer.