Cancer Immunotherapy by Targeting A2 Adenosine Receptor

描述(由申请人提供)：本提案的主要目标是提供肿瘤微环境(TME)中低氧腺苷能免疫抑制的分子机制。这项研究作为基础癌症免疫学研究的一部分，对于开发有前景的新型抗缺氧-腺苷能免疫疗法具有重要意义。这些方案需要不断改进和优化，以帮助当前的临床应用。这项拟议的研究将调查由肿瘤反应性T细胞表面的免疫抑制A2A腺苷受体(A2AR)控制的分子和细胞事件。阻止A2AR介导的肿瘤反应性T细胞抑制可能是实现肿瘤排斥反应的关键。到目前为止，我们的研究已经证实，是肿瘤缺氧产生的胞外腺苷和A2AR腺苷受体介导的免疫抑制的细胞内cAMP升高抑制了抗肿瘤T淋巴细胞。研究表明，A2AR基因靶向或A2AR拮抗剂均可阻止T细胞的抑制，并使肿瘤排斥反应和生存得以实现。这导致了对降低肿瘤产生的腺苷和A2AR信号水平的新方法的考虑。为此，我们测试并确认了补充氧气(40-60%)的概念上的新医学用途，以防止免疫抑制的细胞外腺苷在TME中积聚。我们的观察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的免疫治疗方案与40%或60%的氧气呼吸和天然A2AR拮抗剂茶碱相结合。本研究的目的是通过肿瘤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，确定低氧-A2AR-腺苷能通路在肿瘤排斥反应的分子和细胞机制中的作用。在我们的新目标1中，我们将研究A2AR对抗肿瘤免疫的生理性免疫抑制在多大程度上与和/或控制免疫负性调节因子。在目标2、3中，我们将建立联合肿瘤疫苗和CTLA-4抗体阻断的抗A2AR-腺苷能抗肿瘤治疗的上限，并阐明靶向A2AR对肿瘤反应性T细胞和髓系细胞的分子和免疫学后果。预计这些研究将确定低氧-A2AR-腺苷能免疫抑制如何防止肿瘤排斥反应，并使患者能够存活并对排斥肿瘤进行长期免疫记忆。这反过来将为抗缺氧-A2AR-腺苷能临床方案提供优越的设计。 公共卫生相关性：在这项研究中，我们正在使用小鼠癌症模型来开发一种新的癌症治疗方法，以提高免疫系统摧毁肿瘤的能力。这种疗法的作用是使肿瘤的保护机制失效，从而使人体的免疫系统能够杀死肿瘤。希望与患者正在进行的癌症治疗结合使用，这种疗法最终可能会改善肿瘤的排斥反应，提高存活率，并在患者体内创建免疫记忆，以保护其免受癌症复发。预计这种免疫疗法将提高目前癌症治疗的有效性，并降低几种癌症的发病率和死亡率。

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. PUBLIC HEALTH RELEVANCE: In this study, we are using mouse cancer models to develop a novel cancer therapy that improves the ability of the immune system to destroy tumors. This therapy acts by deactivating the tumor's protective mechanism thereby enabling the body's immune system to kill the tumor. The hope is that, used in conjunction with the person's ongoing cancer treatment, this therapy may eventually improve rejection of the tumor, increase survival, and create an immunological memory in the patient's body to protect it from cancer recurrence. It is anticipated that this immunotherapy will increase the effectiveness of current cancer treatments and decrease morbidity and mortality in several forms of cancer.