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Cancer Immunotherapy by Targeting A2 Adenosine Receptor

靶向 A2 腺苷受体的癌症免疫治疗

基本信息

批准号：
9068777
负责人：
Michail Sitkovsky
金额：
$ 21.44万
依托单位：
NORTHEASTERN UNIVERSITY
依托单位国家：
美国
项目类别：
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/9068777
关键词：
ADORA2A gene Adenosine Adenosine A2 Receptors 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 Cytotoxic T-Lymphocyte-Associated Protein 4 Data Development Effectiveness Europe Event Gene Deletion Generations Genetic Genetic study 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 transgenic adenocarcinoma of mouse prostate tumor tumor microenvironment

项目摘要

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.

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制的理解。这项研究作为基础癌症免疫学研究的一部分以及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，以协助当前转化为临床。拟议的研究将调查肿瘤反应性 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。防止 A2AR 介导的肿瘤反应性 T 细胞抑制对于实现肿瘤排斥至关重要。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升高抑制了抗肿瘤T淋巴细胞。事实证明，A2AR 基因靶向或 A2AR 拮抗剂可以防止 T 细胞的抑制，并使肿瘤排斥和存活。这导致人们考虑采用新方法来降低肿瘤产生的腺苷和 A2AR 信号传导水平。为此，我们测试并证实了补充氧气 (40-60%) 的概念新颖的医疗用途，以防止 TME 中免疫抑制细胞外腺苷的积累。我们的观察结果促使美国和俄罗斯的临床医生科学家将他们现有的癌症患者免疫治疗方案与 40% 或 60% 氧气呼吸和天然 A2AR 拮抗剂茶碱治疗结合起来。该提案的目的是确定缺氧-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 抗肿瘤免疫的生理免疫抑制与免疫负调节因子协作和/或控制的程度。在目标 2、3 中，我们将确定抗 A2AR 腺苷能抗肿瘤治疗与癌症疫苗和 CTLA-4 抗体阻断相结合的上限，并阐明靶向 A2AR 对肿瘤反应性 T 细胞和骨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实现针对被排斥肿瘤的生存和长期免疫记忆。反过来，这将为抗缺氧-A2AR-腺苷能临床方案提供卓越的设计。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Design and evaluation of xanthine based adenosine receptor antagonists: potential hypoxia targeted immunotherapies.

基于黄嘌呤的腺苷受体拮抗剂的设计和评估：潜在的缺氧靶向免疫疗法。

DOI：
10.1016/j.bmc.2013.09.043
发表时间：
2013
期刊：
Bioorganic & medicinal chemistry
影响因子：
3.5
作者：
Thomas,Rhiannon;Lee,Joslynn;Chevalier,Vincent;Sadler,Sara;Selesniemi,Kaisa;Hatfield,Stephen;Sitkovsky,Michail;Ondrechen,MaryJo;Jones,GrahamB
通讯作者：
Jones,GrahamB

Oxygenation to improve cancer vaccines, adoptive cell transfer and blockade of immunological negative regulators.

DOI：
10.1080/2162402x.2015.1052934
发表时间：
2015-12
期刊：
Oncoimmunology
影响因子：
7.2
作者：
Hatfield SM;Sitkovsky M
通讯作者：
Sitkovsky M

Germinal Center Hypoxia Potentiates Immunoglobulin Class Switch Recombination.

DOI：
10.4049/jimmunol.1601401
发表时间：
2016-11-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
0
作者：
Abbott RK;Thayer M;Labuda J;Silva M;Philbrook P;Cain DW;Kojima H;Hatfield S;Sethumadhavan S;Ohta A;Reinherz EL;Kelsoe G;Sitkovsky M
通讯作者：
Sitkovsky M

Analytical tools for characterizing biopharmaceuticals and the implications for biosimilars.