"Cancer Immunotherapy by Targeting A2 Adenosine Receptor"

“针对 A2 腺苷受体的癌症免疫疗法”

• 批准号: 7236729
• 负责人: Michail Sitkovsky
• 金额: $ 21.65万
• 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 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7236729
• 关键词: Adenosine; Adenosine A2 Receptors; Adoptive Transfer; Area; Cancerous; Cells; Coupled; Data; Genes; Genetic; Goals; Hypoxia; Immune; Immune response; Immunosuppressive Agents; Immunotherapeutic agent; Immunotherapy; In Vitro; Lead; Life; Liver; Lung; Mediating; Modeling; Mus; Normal tissue morphology; Operative Surgical Procedures; Play; Proteins; Protocols documentation; Radiation therapy; Resistance; Role; Solid Neoplasm; Surface; T-Lymphocyte; Testing; Tissues; cancer immunotherapy; cancer therapy; chemotherapy; human ADORA2A protein; immunogenic; improved; in vivo; novel; prevent; receptor; tumor

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（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。该提案的总体目标是通过灭活抑制肿瘤附近或肿瘤内抗肿瘤 T 细胞的机制，使癌症免疫疗法更加有效。该提案的中心假设是，免疫抑制性 Gs 蛋白偶联 A2 腺苷受体亚型 A2A 和 A2B（分别为 A2AR 和 A2BR）的基因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得出的，即 A2AR 和 A2BR 在保护正常组织（例如肝脏和肺）免受急性炎症和缺氧区域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设，证明了对大肿瘤的完全或显着改善的排斥反应大约在 -60% 的小鼠 A2AR 基因失活。我们的数据强烈表明，为了消除 100% 小鼠的肿瘤保护作用，A2AR 和 A2BR 都应该被灭活。在这里，我们建议利用这一新的认识，通过使抗肿瘤 T 细胞对肿瘤产生的腺苷的抑制具有抵抗力，来实现对肿瘤的完全排斥。这将通过在小鼠中基因删除 A2AR 和 A2BR 来完成，或者通过用针对 A2AR 和 A2BR 的新型拮抗剂治疗荷瘤小鼠，或者通过在体外扩增过程中对“可抑制的”抗肿瘤 T 细胞进行阴性选择来完成。独特类型的小鼠（缺乏 A2AR 或 A2BR 或两者）将用于测试这种新颖且可行的策略，以改善癌症的免疫治疗。