"Cancer Immunotherapy by Targeting A2 Adenosine Receptor"

“针对 A2 腺苷受体的癌症免疫疗法”

• 批准号: 7100600
• 负责人: Michail Sitkovsky
• 金额: $ 22.29万
• 依托单位: NORTHEASTERN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-05-26 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7100600
• 关键词: neoplasm /cancer; neoplasm /cancer immunotherapy; purinergic receptor

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.

描述（由申请人提供）：据信癌症免疫疗法的应用受到限制，因为抗肿瘤T细胞在实体瘤的免疫抑制微环境中受到抑制。该建议的总体目标是通过灭活肿瘤附近或肿瘤内抗肿瘤T细胞的机制来使癌症免疫疗法更有效。该提议的中心假设是，遗传缺失或药理学失活的免疫抑制，GS蛋白偶联的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，从而抑制其完整的反应。我们较早的发现引起了这一假设，即A2AR和A2BR在保护正常组织（例如肝脏和肺）免受急性发炎和低氧区域中过度活跃的免疫细胞的保护中起关键作用。我们的初步结果证明了这一假设，证明了大约完全或大致排斥的大肿瘤的排斥 -60％遗传灭活A2AR的小鼠。我们的数据强烈表明，应灭活A2AR和A2BR，以消除100％小鼠的肿瘤保护。在这里，我们建议利用这种新的理解，通过使抗肿瘤的T细胞对肿瘤产生的腺苷抗抑制作用，从而完全排斥肿瘤。这将通过小鼠A2AR和A2BR的遗传缺失，或通过对A2AR和A2BR选择性的新型拮抗剂或通过在体外扩张期间选择“可约束”抗肿瘤T细胞的新型拮抗剂的肿瘤小鼠进行的。在A2AR或A2BR或两者中缺乏小鼠的独特类型将用于测试这种新颖且可行的策略，以改善癌症的免疫疗法。