"Cancer Immunotherapy by Targeting A2 Adenosine Receptor"

1RO1 CA111985-01 标题：靶向A2腺苷受体的癌症免疫治疗。 据认为，癌症免疫治疗的应用受到限制，因为抗肿瘤T细胞被抑制在 实体瘤的免疫抑制微环境。这项提案的总体目标是将 肿瘤免疫治疗更有效的方法是灭活抑制T细胞附近抗肿瘤细胞的机制。 在肿瘤内。这一建议的中心假设是基因缺失或药物失活 在免疫抑制方面，Gs蛋白偶联A2腺苷受体亚型A2A和A2B(A2AR和 A2BR)应防止抗肿瘤T细胞的抑制，从而促进其完全 拒绝。这一假说是由我们早先的发现推动的，即A2AR和A2BR在 保护正常组织(如肝脏和肺)免受急性炎症和严重炎症时过度活跃的免疫细胞的影响 缺氧区。我们的初步结果证实了这一假设，证明了完全或大部分 通过基因失活的A2AR改善-60%小鼠的大肿瘤排斥反应。我们的数据非常强大 建议A2AR和A2BR都应灭活，以消除100%的肿瘤保护 老鼠。在这里，我们建议利用这一新的理解来实现完全拒绝 通过使抗肿瘤T细胞抵抗肿瘤产生的腺苷的抑制来治疗肿瘤。这将是 通过在小鼠中同时缺失A2AR和A2BR的基因，或通过对荷瘤小鼠进行 选择性A2AR和A2BR或阴性选择“可抑制”抗肿瘤T的新型拮抗剂 细胞在体外扩增过程中。独特类型的小鼠-A2AR或A2BR缺陷或两者都缺乏？将用于 测试这一新颖而可行的策略，以提高癌症的免疫治疗。

1RO1 CA111985-01 Title: Cancer immunotherapy by targeting A2 adenosine receptor. 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 -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.