腺苷对肿瘤获得性免疫的抑制作用及干预策略

Inhibitory effect of adenosine on adaptive antitumor immunity and intervention strategies

以肿瘤微环境中缺少免疫细胞浸润为特征的“冷肿瘤”通常对免疫治疗的响应性低,探究“冷肿瘤”形成的原因并进行干预,从而将其变成“热肿瘤”是提高免疫治疗疗效的重要策略。作为腺苷三磷酸的水解产物,腺苷在肿瘤微环境中的浓度显著高于正常组织,对肿瘤获得性免疫具有抑制作用。肿瘤细胞、树突状细胞、巨噬细胞及T淋巴细胞的表面有丰富的腺苷受体,腺苷与受体结合后可以启动下游信号通路来抑制肿瘤的抗原提呈和免疫细胞活化,从而抑制肿瘤的获得性免疫。腺苷可下调树突状细胞和巨噬细胞上主要组织相容性复合体Ⅱ和共刺激因子的表达,从而抑制抗原向T淋巴细胞的提呈。腺苷抑制T淋巴细胞上T细胞受体与配体结合和跨膜信号传导,同时能抑制抗肿瘤细胞因子分泌从而抑制T淋巴细胞的激活。腺苷也通过抑制趋化因子的分泌和KCa3.1通道从而抑制效应T淋巴细胞运输至肿瘤部位并浸润。此外,腺苷通过促进免疫抑制性细胞因子的分泌、增加免疫检查点蛋白表达、提高免疫抑制性细胞的活性等途径遏制细胞毒性T细胞对肿瘤细胞的杀伤作用。鉴于腺苷对肿瘤获得性免疫的抑制作用,目前已有多种抑制腺苷生成或阻断腺苷受体的抑制剂正处于临床前或临床研发阶段,旨在增强其他免疫疗法的效果。本文总结分析腺苷对肿瘤获得性免疫的抑制作用及分子机制,并对抑制腺苷途径在抗肿瘤免疫中的最新应用进展进行综述。

Tumors in which the microenvironment is characterized by lack of immune cell infiltration are referred as“cold tumors”and typically exhibit low responsiveness to immune therapy.Targeting the factors contributing to“cold tumors”formation and converting them into“hot tumors”is a novel strategy for improving the efficacy of immunotherapy.Adenosine,a hydrolysis product of ATP,accumulates with a significantly higher concentration in the tumor microenvironments compared with normal tissue and exerts inhibitory effects on tumor-specific adaptive immunity.Tumor cells,dendritic cells,macrophages,and T cells express abundant adenosine receptors on their surfaces.The binding of adenosine to these receptors initiates downstream signaling pathways that suppress tumor antigen presentation and immune cell activation,consequently dampening adaptive immune responses against tumors.Adenosine down-regulates the expression of major histocompatibility complexⅡand co-stimulatory factors on dendritic cells and macrophages,thereby inhibiting antigen presentation to T cells.Adenosine also inhibits ligand-receptor binding and transmembrane signaling on T cells,concomitantly suppressing the secretion of anti-tumor cytokines and impairing T cell activation.Furthermore,adenosine hinders effector T cell trafficking to tumor sites and infiltration by inhibiting chemokine secretion and KCa3.1 channels.Additionally,adenosine promotes the secretion of immunosuppressive cytokines,increases immune checkpoint protein expression,and enhances the activity of immunosuppressive cells,collectively curbing cytotoxic T cell-mediated tumor cell killing.Given the immunosuppressive role of adenosine in adaptive antitumor immunity,several inhibitors targeting adenosine generation or adenosine receptor blockade are currently in preclinical or clinical development with the aim of enhancing the effectiveness of immunotherapies.This review provides an overview of the inhibitory effects of adenosine on adaptive antitumor immunity,elucidate the molecular mechanisms involved,and summarizes the latest advances in application of adenosine inhibition strategies for antitumor immunotherapy.