"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，癌症免疫治疗应用是有限的，因为抗肿瘤T细胞在实体瘤的免疫抑制微环境中受到抑制。该提案的总体目标是通过灭活抑制肿瘤附近或肿瘤内的抗肿瘤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免疫抑制性Gs蛋白偶联A2腺苷受体亚型A2 A和A2 B（分别为A2 AR和A2 BR）的遗传缺失或药理学失活应防止抗肿瘤T细胞的抑制，从而促进其完全排斥。这一假设是由我们早期的发现所提示的，即A2 AR和A2 BR在保护正常组织（例如，肝脏和肺）从急性发炎和缺氧区域的过度活跃的免疫细胞中。我们的初步结果证实了这一假设，表明完全或大大改善了大肿瘤的排斥反应， ~ 60%的小鼠具有遗传失活的A2 AR。我们的数据强烈表明，A2 AR和A2 BR都应该被灭活，以消除100%小鼠的肿瘤保护作用。在这里，我们建议利用这一新的理解，通过使抗肿瘤T细胞对肿瘤产生的腺苷的抑制具有抗性来实现对肿瘤的完全排斥。这将通过在小鼠中遗传缺失A2 AR和A2 BR，或通过用对A2 AR和A2 BR两者具有选择性的新型拮抗剂治疗荷瘤小鼠，或通过在体外扩增期间阴性选择“可增殖的”抗肿瘤T细胞来完成。A2 AR或A2 BR或两者都缺乏的独特类型的小鼠将用于测试这种新颖可行的策略，以改善癌症的免疫治疗。