Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, 4006, Queensland, Australia.
Diabetes Center, University of California, San Francisco, California 94143, USA.
Nat Rev Cancer. 2017 Dec;17(12):709-724. doi: 10.1038/nrc.2017.86. Epub 2017 Oct 23.
Despite the success of anti-programmed cell death protein 1 (PD1), anti-PD1 ligand 1 (PDL1) and anti-cytotoxic T lymphocyte antigen 4 (CTLA4) therapies in advanced cancer, a considerable proportion of patients remain unresponsive to these treatments (known as innate resistance). In addition, one-third of patients relapse after initial response (known as adaptive resistance), which suggests that multiple non-redundant immunosuppressive mechanisms coexist within the tumour microenvironment. A major immunosuppressive mechanism is the adenosinergic pathway, which now represents an attractive new therapeutic target for cancer therapy. Activation of this pathway occurs within hypoxic tumours, where extracellular adenosine exerts local suppression through tumour-intrinsic and host-mediated mechanisms. Preclinical studies in mice with adenosine receptor antagonists and antibodies have reported favourable antitumour immune responses with some definition of the mechanism of action. Currently, agents targeting the adenosinergic pathway are undergoing first-in-human clinical trials as single agents and in combination with anti-PD1 or anti-PDL1 therapies. In this Review, we describe the complex interplay of adenosine and adenosine receptors in the development of primary tumours and metastases and discuss the merits of targeting one or more components that compose the adenosinergic pathway. We also review the early clinical data relating to therapeutic agents inhibiting the adenosinergic pathway.
尽管抗程序性细胞死亡蛋白 1（PD-1）、抗 PD-1 配体 1（PD-L1）和抗细胞毒性 T 淋巴细胞相关抗原 4（CTLA-4）疗法在晚期癌症中取得了成功，但相当一部分患者对这些治疗仍无反应（称为固有耐药性）。此外，三分之一的患者在初始缓解后复发（称为适应性耐药性），这表明肿瘤微环境中存在多种非冗余的免疫抑制机制。一种主要的免疫抑制机制是腺苷能途径，目前它是癌症治疗的一个有吸引力的新治疗靶点。该途径的激活发生在缺氧肿瘤中，细胞外腺苷通过肿瘤内在和宿主介导的机制发挥局部抑制作用。在具有腺苷受体拮抗剂和抗体的小鼠的临床前研究中，已经报道了具有一定作用机制的抗肿瘤免疫反应。目前，靶向腺苷能途径的药物正在进行首次人体临床试验，作为单一药物以及与抗 PD-1 或抗 PD-L1 治疗联合使用。在这篇综述中，我们描述了腺苷和腺苷受体在原发性肿瘤和转移瘤发展中的复杂相互作用，并讨论了靶向组成腺苷能途径的一个或多个成分的优点。我们还回顾了与抑制腺苷能途径的治疗药物相关的早期临床数据。
