Bloomberg~Kimmel Institute for Cancer Immunotherapy, Sidney-Kimmel Comprehensive Cancer Center, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA.
Johns Hopkins University School of Medicine, 1650 Orleans Street, Room 409, Cancer Research Building 1, Baltimore, MD, 21231, USA.
J Immunother Cancer. 2018 Jun 18;6(1):57. doi: 10.1186/s40425-018-0360-8.
Immune checkpoint antagonists (CTLA-4 and PD-1/PD-L1) and CAR T-cell therapies generate unparalleled durable responses in several cancers and have firmly established immunotherapy as a new pillar of cancer therapy. To extend the impact of immunotherapy to more patients and a broader range of cancers, targeting additional mechanisms of tumor immune evasion will be critical. Adenosine signaling has emerged as a key metabolic pathway that regulates tumor immunity. Adenosine is an immunosuppressive metabolite produced at high levels within the tumor microenvironment. Hypoxia, high cell turnover, and expression of CD39 and CD73 are important factors in adenosine production. Adenosine signaling through the A2a receptor expressed on immune cells potently dampens immune responses in inflamed tissues. In this article, we will describe the role of adenosine signaling in regulating tumor immunity, highlighting potential therapeutic targets in the pathway. We will also review preclinical data for each target and provide an update of current clinical activity within the field. Together, current data suggest that rational combination immunotherapy strategies that incorporate inhibitors of the hypoxia-CD39-CD73-A2aR pathway have great promise for further improving clinical outcomes in cancer patients.
免疫检查点拮抗剂（CTLA-4 和 PD-1/PD-L1）和 CAR T 细胞疗法在多种癌症中产生了无与伦比的持久反应，并使免疫疗法牢固确立为癌症治疗的新支柱。为了将免疫疗法的影响扩展到更多的患者和更广泛的癌症类型，针对肿瘤免疫逃逸的其他机制将是至关重要的。腺苷信号转导已成为调节肿瘤免疫的关键代谢途径。腺苷是肿瘤微环境中高水平产生的一种免疫抑制代谢物。缺氧、高细胞周转率以及 CD39 和 CD73 的表达是产生腺苷的重要因素。通过表达在免疫细胞上的 A2a 受体的腺苷信号转导，可强烈抑制炎症组织中的免疫反应。在本文中，我们将描述腺苷信号转导在调节肿瘤免疫中的作用，强调该通路中的潜在治疗靶点。我们还将回顾每个靶点的临床前数据，并提供该领域当前临床活动的最新信息。总之，现有数据表明，合理的联合免疫治疗策略，包括缺氧-CD39-CD73-A2aR 通路抑制剂，有望进一步提高癌症患者的临床疗效。
