文章：

靶向免疫抑制腺苷在癌症中的作用

Targeting immunosuppressive adenosine in cancer

原文发布日期：2017-12-01

DOI: 10.1038/nrc.2017.86

类型: Review Article

开放获取: 否

要点：

1. The adenosinergic pathway encompasses ectonucleotidases (CD39 and CD73) and adenosine receptors (A1R, A2AR, A2BR and A3R) that participate in the generation and signalling of adenosine in the tumour microenvironment (TME), respectively. Of the four adenosine receptors, the cyclic AMP (cAMP)-activating receptors A2AR and A2BR predominantly exert immunosuppressive functions in the TME.
2. Molecules of this pathway are regulated by several immunogenic and genetic drivers. Of these, hypoxia and transforming growth factor-β (TGFβ) represent the key drivers of the adenosinergic pathway.
3. Within a tumour niche, adenosinergic molecules are expressed by tumour cells, stromal cells and immune cells, and their critical point of action is not yet fully understood.
4. Adenosine, through activation of cAMP, can directly regulate tumour proliferation, survival, adhesion and migration. In immune cells, adenosine molecules greatly hamper vital immune effector cell functions and may be involved in mediating T cell exhaustion.
5. Novel antibodies and small molecules targeted to members of the adenosinergic pathway are now reaching clinical trials in patients with advanced cancer and may be combined with standard-of-care therapies and novel immunotherapies.

要点翻译：

1. 腺苷能通路包含外切核苷酸酶（CD39和CD73）和腺苷受体（A1R、A2AR、A2BR和A3R），它们分别参与肿瘤微环境（TME）中腺苷的生成和信号传导。在四种腺苷受体中，激活环磷酸腺苷（cAMP）的A2AR和A2BR受体在肿瘤微环境中主要发挥免疫抑制功能。
2. 该通路中的分子受到多种免疫原性和遗传驱动因素的调控。其中，缺氧和转化生长因子-β（TGFβ）是腺苷能通路的关键驱动因素。
3. 在肿瘤微环境中，腺苷能分子由肿瘤细胞、基质细胞和免疫细胞表达，其关键作用机制尚未完全明确。
4. 腺苷通过激活cAMP可直接调控肿瘤的增殖、存活、黏附和迁移。在免疫细胞中，腺苷分子会严重阻碍关键免疫效应细胞的功能，并可能参与介导T细胞耗竭。
5. 针对腺苷能通路成员的新型抗体和小分子药物目前已进入晚期癌症患者的临床试验阶段，这些疗法可能与标准治疗方案及新型免疫疗法联合使用。

英文摘要：

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.

摘要翻译： 

尽管抗程序性死亡蛋白1（PD1）、抗PD1配体1（PDL1）和抗细胞毒性T淋巴细胞抗原4（CTLA4）疗法在晚期癌症中取得成功，但仍有相当比例的患者对这些治疗无反应（称为先天耐药）。此外，三分之一的患者在初始应答后复发（称为获得性耐药），这提示肿瘤微环境内存在多种非冗余的免疫抑制机制。腺苷能通路是主要的免疫抑制机制之一，现已成为癌症治疗中颇具吸引力的新靶点。该通路的激活发生于缺氧肿瘤中，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。小鼠临床前研究显示，使用腺苷受体拮抗剂和抗体可产生有利的抗肿瘤免疫应答，并部分阐明其作用机制。目前，靶向腺苷能通路的药物正作为单药或联合抗PD1/PDL1疗法进行首次人体临床试验。本文综述了腺苷及其受体在原发瘤和转移灶发展中的复杂相互作用，讨论了靶向腺苷能通路一个或多个组分的优势，并回顾了抑制该通路的早期临床数据。

原文链接：

Targeting immunosuppressive adenosine in cancer