靶向腺苷A_(2A)受体的肿瘤免疫治疗研究进展  

Progress for targeting adenosine A_(2A) receptors in cancer immunotherapy

作　　者：张芷菁 张启怡 金祖翼 朱凯[2] 丁文 张小雷 ZHANG Zhi-jing;ZHANG Qi-yi;JIN Zu-yi;ZHU Kai;DING Wen;ZHANG Xiao-lei(School of Pharmaceutical Sciences,Sun Yat-sen University,Guangzhou 510006,China;Changchun University of Chinese Medicine,Changchun 130117,China)

机构地区：[1]中山大学药学院,广东广州510006 [2]长春中医药大学,吉林长春130117

出　　处：《药学学报》2022年第9期2557-2569,共13页Acta Pharmaceutica Sinica

基　　金：国家自然科学基金资助项目(81973359);广东省基础与应用基础研究基金(2022A1515012204);广州市科技计划项目-基础与应用基础研究项目(202002030408,202103000097);吉林省科技发展计划项目(20200404105YY,20210204055YY).

摘　　要：虽然免疫治疗现已成为对抗恶性肿瘤的革命性策略,但应答率不高,易产生耐受仍是制约肿瘤免疫治疗临床深入应用的瓶颈。不少研究表明,免疫抑制型肿瘤微环境和复杂的免疫逃逸机制是影响免疫检查点治疗效果和应答率的重要因素。因此,逆转肿瘤微环境障碍是提高免疫治疗应答率的关键。在肿瘤微环境中,胞外腺苷高水平的积累对免疫应答的抑制作用受到人们越来越多的关注。靶向腺苷受体,尤其是A_(2A)R亚型,可能是激活免疫应答、提高免疫治疗效果的有效策略。靶向腺苷-A_(2A)R通路可以增加免疫浸润,增强免疫细胞功能,将对免疫治疗不敏感的“冷肿瘤”部分逆转为“热肿瘤”,以增强治疗应答率并提高当前免疫治疗的疗效。目前,有不少的腺苷受体抑制剂已经在临床试验中显示出良好的效果,特别是与免疫检查点抑制剂、化疗和获得性细胞疗法的药物联用,有望为肿瘤免疫治疗带来新的突破。本文综述了肿瘤微环境中腺苷积累的方式、腺苷A_(2A)受体的作用和调控机制、腺苷A_(2A)受体抑制剂的临床试验进展和用药策略、靶向腺苷A_(2A)受体的潜在风险及其应用前景。Immunotherapy has completely changed the paradigm of clinical tumor treatment,but immune checkpoint inhibitors still have low objective response rates and are prone to drug resistance for most solid tumors.The immune suppression tumor microenvironment and complicated tumor immune escape mechanisms are key factors that affect the clinical outcome and response rates.Therefore,it is critical to reverse the obstacle of the tumor microenvironment to improve immunotherapy efficacy.The immune suppression caused by the increased level of adenosine in the tumor microenvironment raises the attention of people.Targeting adenosine receptors,especially A_(2A)R,will be an effective strategy to improve immunotherapy efficacy.Targeting the adenosine-A_(2A)pathway can increase immune infiltration,enhance immune cell function,and partially reverse immunotherapyinsensitive"cold tumors"to"hot tumors"to enhance treatment response rates and improve the efficacy of current immunotherapy.At present,many adenosine receptor inhibitors have shown good results in clinical trials,especially in combination with immune checkpoint inhibitors,chemotherapy,and adoptive cell transfer therapeutic drugs,which are expected to be used for tumor immunotherapy to bring new breakthroughs.This article reviews the accumulation mode of adenosine in the tumor microenvironment,the role of A_(2A)R and their regulatory mechanism in immune response,the progress of A_(2A)R inhibitors in clinical trials,potential risks to target A_(2A)R,and the prospects for therapeutic targeting A_(2A)R.

关 键 词：免疫治疗 肿瘤微环境 腺苷受体 A_(2A)R抑制剂 肿瘤免疫治疗药物 

分 类 号：R943[医药卫生—药剂学]