"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。 据信，癌症免疫治疗应用是有限的，因为抗肿瘤T细胞在肿瘤细胞中被抑制。 实体瘤的免疫抑制微环境。该提案的总体目标是使 癌症免疫疗法通过灭活抑制抗肿瘤T细胞的机制更有效， 在肿瘤中。这一建议的中心假设是基因缺失或药理失活 免疫抑制性的Gs蛋白偶联A2腺苷受体亚型A2 A和A2 B（A2 AR和A2 B）， A2 BR）应防止抗肿瘤T细胞的抑制，从而促进它们的完全活化。 排斥反应这一假设是由我们早期的发现所提示的，即A2 AR和A2 BR在以下方面起着关键作用： 保护正常组织（例如，肝脏和肺）从过度活跃的免疫细胞在急性炎症和 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的 在基因失活的A2 AR小鼠中，约60%的大肿瘤的排斥反应得到改善。我们的数据显示 这表明A2 AR和A2 BR都应该被灭活，以消除100%的肿瘤保护作用。 小鼠在这里，我们建议利用这种新的理解来完成完全拒绝 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 通过在小鼠中基因缺失A2 AR和A2 BR，或通过用 对A2 AR和A2 BR都具有选择性或通过“可重复的”抗肿瘤T细胞的阴性选择的新拮抗剂 细胞在体外扩增过程中。将使用A2 AR或A2 BR或两者均缺乏的独特类型的小鼠， 测试这种新的和可行的策略，以改善癌症的免疫治疗。

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.