Cancer Immunotherapy by Targeting A2 Adenosine Receptor

描述（由申请人提供）：本提案的总体目标是提供肿瘤微环境（TME）中缺氧-腺苷能免疫抑制的分子机制理解。这项研究是癌症免疫学基础研究的重要组成部分，也是开发有前途的新型抗缺氧-腺苷能免疫疗法的重要组成部分。这些方案需要不断改进和优化，以协助当前的临床翻译。拟议的研究将研究由肿瘤反应性T细胞表面的免疫抑制性A2A腺苷受体（A2AR）控制的分子和细胞事件。防止a2ar介导的肿瘤反应性T细胞抑制可能是促进肿瘤排斥反应的关键。在我们目前的研究中，已经确定是肿瘤缺氧产生的细胞外腺苷和A2AR腺苷受体介导的细胞内免疫抑制性cAMP的升高抑制了抗肿瘤t淋巴细胞。研究表明，无论是A2AR基因靶向还是A2AR拮抗剂，都能阻止T细胞的抑制，并使肿瘤产生排斥反应和存活。这导致考虑采用新方法来降低肿瘤产生的腺苷和A2AR信号的水平。为此，我们测试并证实了补充氧气（40-60%）在医学上的新概念，以防止TME中免疫抑制细胞外腺苷的积累。我们的观察结果刺激了美国和俄罗斯的临床科学家将他们现有的癌症患者40%或60%氧气呼吸和天然A2AR拮抗剂茶碱治疗的免疫治疗方案结合起来。本研究的目的是确定缺氧- a2ar -腺苷能通路在癌症疫苗诱导的肿瘤反应性T细胞和过继转移的肿瘤反应性T细胞的肿瘤排斥反应的分子和细胞机制中的作用。在我们新的Aim 1中，我们将研究A2AR抗肿瘤免疫的生理性免疫抑制在多大程度上协同和/或控制免疫负调节因子。在Aims 2,3中，我们将建立抗A2AR-腺苷能抗肿瘤治疗联合癌症疫苗和CTLA-4抗体阻断的上限，并阐明靶向A2AR对肿瘤反应性T细胞和髓细胞的分子和免疫学后果。预计这些研究将确定缺氧- a2ar -腺苷能免疫抑制如何防止肿瘤排斥，并使肿瘤存活和长期免疫记忆。反过来，这将提供抗缺氧- a2ar -腺苷能临床方案的优越设计。

DESCRIPTION (provided by applicant): The overarching goal of this proposal is to provide the molecular mechanistic understanding of hypoxia- adenosinergic immunosuppression in the tumor microenvironment (TME). This research is important as part of fundamental cancer immunology studies and for the development of promising, novel anti-hypoxia- adenosinergic immunotherapy. These protocols require continuous improvement and optimization to assist current translation into the clinic. The proposed research will investigate molecular and cellular events that are controlled by immunosuppressive A2A adenosine receptors (A2AR) on the surface of tumor-reactive T cells. Preventing A2AR-mediated inhibition of tumor-reactive T cells may be critical for enabling tumor rejection. In our studies so far, it was established that it is the tumor hypoxia-produced extracellular adenosine and the A2AR adenosine receptor-mediated elevation of immunosuppressive intracellular cAMP that inhibit anti-tumor T-lymphocytes. It was demonstrated that either A2AR genetic targeting or A2AR antagonists prevent inhibition of T cells and enable tumor rejection and survival. This led to considerations of novel methods to lower levels of tumor-produced adenosine and A2AR signaling. To this end, we tested and confirmed the conceptually novel medical use of supplemental oxygen (40-60%) to prevent accumulation of immunosuppressive extracellular adenosine in the TME. Our observations stimulated clinician-scientists in the USA and Russia to combine their existing immunotherapy protocols of cancer patients with 40% or 60% oxygen breathing and treatment with the natural A2AR antagonist theophylline. The aims of this proposal are to establish the role of the hypoxia-A2AR-adenosinergic pathway in molecular and cellular mechanisms of tumor rejection by cancer vaccine-induced tumor-reactive T cells and by adoptively transferred tumor-reactive T cells. In our new Aim 1, we will investigate the extent by which physiological immunosuppression of anti-tumor immunity by A2AR collaborates with and/or controls immunological negative regulators. In Aims 2, 3, we will establish the upper limit of anti-A2AR-adenosinergic anti-tumor treatment in combination with cancer vaccines and CTLA-4 antibody blockade and clarify the molecular and immunological consequences of targeting A2AR on tumor-reactive T cells and myeloid cells. It is expected that these studies will determine how hypoxia-A2AR-adenosinergic immunosuppression prevents tumor rejection and enables survival and long-term immunological memory against rejected tumors. This, in turn, will provide superior design of anti-hypoxia-A2AR-adenosinergic clinical protocols.