Cancer Immunotherapy by Targeting A2 Adenosine Receptor

靶向 A2 腺苷受体的癌症免疫治疗

• 批准号: 8237886
• 负责人: Michail Sitkovsky
• 金额: $ 21.44万
• 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 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8237886
• 关键词: Adenosine; Adenosine A2 Receptors; Adenosine A2A Receptor; Adenosine A2B Receptor; Adjuvant; Affinity; Antibodies; Antigens; Binding; Breathing; CD8B1 gene; Cancer Immunology Science; Cancer Model; Cancer Patient; Cancer Vaccines; Cells; Clinic; Clinical Protocols; Cyclic AMP; Data; Development; Effectiveness; Europe; Event; Gene Deletion; Generations; Genetic; Goals; HIF1A gene; Hypoxia; Immune response; Immune system; Immunologic Memory; Immunosuppression; Immunosuppressive Agents; Immunotherapy; Malignant Neoplasms; Mediating; Medical; Memory; Methods; Molecular; Morbidity - disease rate; Mus; Myelogenous; Myeloid Cells; Natural Killer Cells; Oxygen; Pathway interactions; Patients; Persons; Pharmaceutical Preparations; Physiological; Protein Isoforms; Protocols documentation; Purinergic P1 Receptors; Receptor Gene; Receptor Signaling; Regulation; Regulatory T-Lymphocyte; Research; Role; Russia; Scientist; Signal Transduction; Suppressor-Effector T-Lymphocytes; Surface; T cell regulation; T-Lymphocyte; Testing; Theophylline; Transgenic Mice; Translating; Translations; Tumor Immunity; Vaccines; base; cancer immunotherapy; cancer recurrence; cancer therapy; clinical application; design; extracellular; hypoxia inducible factor 1; improved; killings; knock-down; mortality; mouse model; novel; prevent; research study; tumor

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.

描述（由申请人提供）：该提案的总体目标是提供对肿瘤微环境（TME）中缺氧 - 腺苷能免疫抑制的分子机械理解。这项研究是基本癌症免疫学研究的一部分以及有前途的，新型抗高氧腺苷能免疫疗法的一部分。这些方案需要持续改进和优化，以帮助当前转化为诊所。拟议的研究将研究由肿瘤反应性T细胞表面上的免疫抑制A2A腺苷受体（A2AR）控制的分子和细胞事件。防止A2AR介导的抑制肿瘤反应性T细胞可能对实现肿瘤排斥反应至关重要。在我们迄今为止的研究中，已经确定是肿瘤缺氧产生的细胞外腺苷和A2AR腺苷受体介导的免疫抑制性细胞内cAMP的升高，抑制了抗肿瘤T-淋巴细胞。事实证明，A2AR遗传靶向或A2AR拮抗剂可以防止T细胞抑制，并启用肿瘤排斥和存活。这导致考虑了新的方法，以降低肿瘤产生的腺苷和A2AR信号传导。为此，我们测试并确认了补充氧（40-60％）的概念上新型医学使用，以防止TME中免疫抑制性细胞外腺苷的积累。我们的观察结果刺激了美国和俄罗斯的临床医生科学家，将其现有的免疫治疗方案结合在一起，以40％或60％的氧气呼吸和使用天然A2AR拮抗剂Theophylline结合使用40％或60％的氧气呼吸和治疗。该提案的目的是确定通过癌症疫苗诱导的肿瘤反应性T细胞以及通过过继转移的肿瘤反应性T细胞来确定肿瘤诱导的肿瘤反应性T细胞中缺氧-A2AR-腺苷能途径在肿瘤排斥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免疫抑制的程度，与和/或控制免疫阴性调节剂和/或控制。在AIM 2、3中，我们将建立抗A2AR-腺苷能抗肿瘤治疗的上限，结合癌症疫苗和CTLA-4抗体阻断，并阐明靶向A2AR在肿瘤反应性T细胞和髓细胞细胞上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，并使抑制肿瘤的生存和长期免疫记忆能力。反过来，这将为抗避风氧-A2AR-腺苷能临床方案提供卓越的设计。 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开发一种新型的癌症疗法，从而提高了免疫系统破坏肿瘤的能力。该疗法通过停用肿瘤的保护机制，从而使人体的免疫系统杀死肿瘤。希望是，与该人正在进行的癌症治疗结合使用，这种疗法最终可能会改善对肿瘤的排斥，增加生存率并在患者体内产生免疫记忆，以保护其免受癌症的复发。预计这种免疫疗法将提高当前癌症治疗的有效性，并降低几种癌症的发病率和死亡率。