药学学报

Drug name	Indication	Sponsor	Phase	Intervention/treatment	Clinical trial identifier
Ciforadenant (CPI-444)	Multiple myeloma	Corvus	Ib	+ Daratumumab	NCT04280328
NSCLC/RCC/CRC/TNBC/cervical cancer/OC/PC/endometrial cancer/sarcoma/HNSCC/bladder cancer/mCRPC/non-hodgkin lymphoma	Corvus	Ⅰ/Ⅰb	+ CPI-006	NCT03454451
RCC/mCRPC	Corvus	Ⅰ/Ⅰb	Single agent/+ atezolizumab	NCT02655822
NSCLC	Corvus	Ⅰb/Ⅱ	+ atezolizumab	NCT03337698
AZD4635	Advanced solid malignancies	AstraZeneca	Ⅰ	Single agent	NCT03980821
Advanced solid malignancies/NSCLC/mCRPC/CRC	AstraZeneca	Ⅰ	Single agent/+ durvalumab/enzalutamide/abiraterone acetate/durvalumab + oleclumab/docetaxel	NCT02740985
Prostate cancer/mCRPC	AstraZeneca	Ⅱ	+ Durvalumab/+ oleclumab/+ durvalumab + oleclumab	NCT04089553
mCRPC	AstraZeneca	Ⅱ	+ Durvalumab/+ durvalumab + cabazitaxel	NCT04495179
Carcinoma/NSCLC	AstraZeneca	Ⅰb/Ⅱ	+ MEDI9447	NCT03381274
PBF-509 (NIR178)	NSCLC	Palobiofarma	Ⅰ/Ⅰb	Single agent/+ PDR001	NCT02403193
NSCLC/TNBC/PDAC/MSS/OC/RCC/mCPRC	Novartis	Ⅰ	+ NZV930/PDR001	NCT03549000
Solid tumors	Novartis	Ⅰ	+ KAZ954	NCT04237649
TNBC	Novartis	Ⅰ	+ PDR001/LAG525	NCT03742349
NSCLC/RCC/pancreatic cancer/urothelial cancer/head and neck cancer/DLBCL/MSS/ TNBC/melanoma	Novartis	Ⅱ	+ PDR001	NCT03207867
RCC	Novartis	Ⅰ/Ⅰb	+ PDR001+ DFF332	NCT04895748
Etrumadenant(AB928)	Metastatic castration-resistant prostate cancer/prostate cancer	Surface Oncology	Ⅱ	+ SRF617 + zimberelimab	NCT05177770
NSCLC/HNSCC/breast cancer/CRC/melanoma/bladder cancer/OC/endometrial cancer/merkel cell carcinoma/gastroesophageal cancer/renal cell carcinoma/CRPC	Arcus	Ⅰ	+ Zimberelimab	NCT03629756
Head and neck cancer/squamous cell carcinoma of head and neck/oral cavity squamous cell carcinoma/oral cavity cancer/oropharynx cancer/oropharynx/squamous cell carcinoma/larynx cancer/pharynx cancer/hypopharynx cancer/hypopharynx squamous cell carcinoma	Arcus	Ib	+ Concurrent cisplatin/+ radiation therapy + zimberelimab	NCT04892875
Metastatic colorectal cancer	Arcus	Ⅰb/Ⅱ	+ Zimberelimab + mFOLFOX-6 + bevacizumab/+ zimberelimab + AB680	NCT04660812
Prostatic neoplasms, castration-resistant/androgen-resistant prostatic neoplasms/castration resistant prostatic neoplasms/prostatic cancer, castration-resistant	Arcus	Ⅰb/Ⅱ	+ Zimberelimab + enzalutamide/+ trumadenant + zimberelimab + docetaxel/+ zimberelimab/+ zimberelimab + AB680/+ AB680	NCT04381832
Gastro esophageal cancer/CRC	Arcus	Ⅰ/Ⅰb	+ mFOLFOX	NCT03720678
TBNC/OC	Arcus	Ⅰ/Ⅰb	+ PLD/+ NP/+ PLD + IPI-549	NCT03719326
NSCLC metastatic/NSCLC/nonsquamous non small cell neoplasm of lung/sensitizing EGFR gene mutation	Arcus	Ⅰ/Ⅰb	+ Carboplatin + pemetrexed/+ carboplatin + pemetrexed + pembrolizumab/+ zimberelimab + carboplatin + pemetrexed	NCT03846310
NSCLC/nonsquamous NSCLC/squamous NSCLC/lung cancer	Arcus	Ⅱ	+ Domvanalimab + zimberelimab	NCT04262856
NSCLC/non-small cell carcinoma	Arcus	Ⅱ	+ Zimberelimab + domvanalimab	NCT04791839
Rectal cancer	Arcus	Ⅱ	+ FOLFOX regimen + zimberelimab	NCT05024097
Prostate adenocarcinoma	Genentech	Ⅱ	+ Atezolizumab	NCT03821246
Pancreatic adenocarcinoma	Roche	Ⅰb/Ⅱ	+ Atezolizumab + chemotherapy	NCT03193190
CRC	Roche	Ⅰb/Ⅱ	Single agent/+ atezolizumab + regorafenib	NCT03555149
Inupadenant (EOS100850)	Solid tumor	iTeos	Ⅰ/Ⅰb	Single agent/+ pembrolizumab/+ chemotherapy	NCT03873883
Solid tumor	iTeos	Ⅰ	Single agent	NCT05117177
Advanced cancer/lung cancer/head and neck cancer/melanoma	iTeos	Ⅰ/Ⅱ	Inupadenant +EOS-448/inupadenant + pembrolizumab	NCT05060432
CS3005	Advanced solid tumors	CStone	Ⅰ	Single agent	NCT04233060
EXS21546	Oncology	Exscientia	Ⅰ	Single agent	NCT04727138
PBF-999	Advanced solid tumor	Palobiofarma	Ⅰ	Single agent	NCT03786484

Drug name	Indication	Sponsor	Phase	Intervention/treatment	Clinical trial identifier
Ciforadenant (CPI-444)	Multiple myeloma	Corvus	Ib	+ Daratumumab	NCT04280328
NSCLC/RCC/CRC/TNBC/cervical cancer/OC/PC/endometrial cancer/sarcoma/HNSCC/bladder cancer/mCRPC/non-hodgkin lymphoma	Corvus	Ⅰ/Ⅰb	+ CPI-006	NCT03454451
RCC/mCRPC	Corvus	Ⅰ/Ⅰb	Single agent/+ atezolizumab	NCT02655822
NSCLC	Corvus	Ⅰb/Ⅱ	+ atezolizumab	NCT03337698
AZD4635	Advanced solid malignancies	AstraZeneca	Ⅰ	Single agent	NCT03980821
Advanced solid malignancies/NSCLC/mCRPC/CRC	AstraZeneca	Ⅰ	Single agent/+ durvalumab/enzalutamide/abiraterone acetate/durvalumab + oleclumab/docetaxel	NCT02740985
Prostate cancer/mCRPC	AstraZeneca	Ⅱ	+ Durvalumab/+ oleclumab/+ durvalumab + oleclumab	NCT04089553
mCRPC	AstraZeneca	Ⅱ	+ Durvalumab/+ durvalumab + cabazitaxel	NCT04495179
Carcinoma/NSCLC	AstraZeneca	Ⅰb/Ⅱ	+ MEDI9447	NCT03381274
PBF-509 (NIR178)	NSCLC	Palobiofarma	Ⅰ/Ⅰb	Single agent/+ PDR001	NCT02403193
NSCLC/TNBC/PDAC/MSS/OC/RCC/mCPRC	Novartis	Ⅰ	+ NZV930/PDR001	NCT03549000
Solid tumors	Novartis	Ⅰ	+ KAZ954	NCT04237649
TNBC	Novartis	Ⅰ	+ PDR001/LAG525	NCT03742349
NSCLC/RCC/pancreatic cancer/urothelial cancer/head and neck cancer/DLBCL/MSS/ TNBC/melanoma	Novartis	Ⅱ	+ PDR001	NCT03207867
RCC	Novartis	Ⅰ/Ⅰb	+ PDR001+ DFF332	NCT04895748
Etrumadenant(AB928)	Metastatic castration-resistant prostate cancer/prostate cancer	Surface Oncology	Ⅱ	+ SRF617 + zimberelimab	NCT05177770
NSCLC/HNSCC/breast cancer/CRC/melanoma/bladder cancer/OC/endometrial cancer/merkel cell carcinoma/gastroesophageal cancer/renal cell carcinoma/CRPC	Arcus	Ⅰ	+ Zimberelimab	NCT03629756
Head and neck cancer/squamous cell carcinoma of head and neck/oral cavity squamous cell carcinoma/oral cavity cancer/oropharynx cancer/oropharynx/squamous cell carcinoma/larynx cancer/pharynx cancer/hypopharynx cancer/hypopharynx squamous cell carcinoma	Arcus	Ib	+ Concurrent cisplatin/+ radiation therapy + zimberelimab	NCT04892875
Metastatic colorectal cancer	Arcus	Ⅰb/Ⅱ	+ Zimberelimab + mFOLFOX-6 + bevacizumab/+ zimberelimab + AB680	NCT04660812
Prostatic neoplasms, castration-resistant/androgen-resistant prostatic neoplasms/castration resistant prostatic neoplasms/prostatic cancer, castration-resistant	Arcus	Ⅰb/Ⅱ	+ Zimberelimab + enzalutamide/+ trumadenant + zimberelimab + docetaxel/+ zimberelimab/+ zimberelimab + AB680/+ AB680	NCT04381832
Gastro esophageal cancer/CRC	Arcus	Ⅰ/Ⅰb	+ mFOLFOX	NCT03720678
TBNC/OC	Arcus	Ⅰ/Ⅰb	+ PLD/+ NP/+ PLD + IPI-549	NCT03719326
NSCLC metastatic/NSCLC/nonsquamous non small cell neoplasm of lung/sensitizing EGFR gene mutation	Arcus	Ⅰ/Ⅰb	+ Carboplatin + pemetrexed/+ carboplatin + pemetrexed + pembrolizumab/+ zimberelimab + carboplatin + pemetrexed	NCT03846310
NSCLC/nonsquamous NSCLC/squamous NSCLC/lung cancer	Arcus	Ⅱ	+ Domvanalimab + zimberelimab	NCT04262856
NSCLC/non-small cell carcinoma	Arcus	Ⅱ	+ Zimberelimab + domvanalimab	NCT04791839
Rectal cancer	Arcus	Ⅱ	+ FOLFOX regimen + zimberelimab	NCT05024097
Prostate adenocarcinoma	Genentech	Ⅱ	+ Atezolizumab	NCT03821246
Pancreatic adenocarcinoma	Roche	Ⅰb/Ⅱ	+ Atezolizumab + chemotherapy	NCT03193190
CRC	Roche	Ⅰb/Ⅱ	Single agent/+ atezolizumab + regorafenib	NCT03555149
Inupadenant (EOS100850)	Solid tumor	iTeos	Ⅰ/Ⅰb	Single agent/+ pembrolizumab/+ chemotherapy	NCT03873883
Solid tumor	iTeos	Ⅰ	Single agent	NCT05117177
Advanced cancer/lung cancer/head and neck cancer/melanoma	iTeos	Ⅰ/Ⅱ	Inupadenant +EOS-448/inupadenant + pembrolizumab	NCT05060432
CS3005	Advanced solid tumors	CStone	Ⅰ	Single agent	NCT04233060
EXS21546	Oncology	Exscientia	Ⅰ	Single agent	NCT04727138
PBF-999	Advanced solid tumor	Palobiofarma	Ⅰ	Single agent	NCT03786484

靶向腺苷A_2A受体的肿瘤免疫治疗研究进展

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张芷菁 ¹ , 张启怡 ¹ , 金祖翼 ¹ , 朱凯 ² , 丁文 ¹^,^* , 张小雷 ¹^,^*

药学学报 | 专题报道：靶向肿瘤免疫治疗策略与药物干预 2022,57(9): 2557-2569

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药学学报 | 专题报道：靶向肿瘤免疫治疗策略与药物干预 2022, 57(9): 2557-2569

靶向腺苷A_2A受体的肿瘤免疫治疗研究进展

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张芷菁¹, 张启怡¹, 金祖翼¹, 朱凯², 丁文¹^,^*, 张小雷¹^,^*

作者信息

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

通讯作者:

*丁文, dingw8@mail2.sysu.edu.cn;

张小雷, Tel: 86-20-39943021, E-mail: zhangxlei5@mail.sysu.edu.cn

Progress for targeting adenosine A_2A receptors in cancer immunotherapy

Zhi-jing ZHANG¹, Qi-yi ZHANG¹, Zu-yi JIN¹, Kai ZHU², Wen DING¹^,^*, Xiao-lei ZHANG¹^,^*

Affiliations

1. School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China

2. Changchun University of Chinese Medicine, Changchun 130117, China

出版时间: 2022-09-12 doi: 10.16438/j.0513-4870.2022-0199

文章导航

摘要

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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_2AR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_2AR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。

关键词

免疫治疗 / 肿瘤微环境 / 腺苷受体 / A_2AR抑制剂 / 肿瘤免疫治疗药物

Abstract

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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_2AR, 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 immunotherapy-insensitive "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_2AR and their regulatory mechanism in immune response, the progress of A_2AR inhibitors in clinical trials, potential risks to target A_2AR, and the prospects for therapeutic targeting A_2AR.

Key words

immunotherapy / tumor microenvironment / adenosine receptor / A_2AR inhibitor / cancer immunotherapy drug

引用本文

张芷菁, 张启怡, 金祖翼, 朱凯, 丁文, 张小雷. 靶向腺苷A_2A受体的肿瘤免疫治疗研究进展. 药学学报, 2022 , 57 (9) : 2557 -2569 . DOI: 10.16438/j.0513-4870.2022-0199

Zhi-jing ZHANG, Qi-yi ZHANG, Zu-yi JIN, Kai ZHU, Wen DING, Xiao-lei ZHANG. Progress for targeting adenosine A_2A receptors in cancer immunotherapy[J]. Acta Pharmaceutica Sinica, 2022 , 57 (9) : 2557 -2569 . DOI: 10.16438/j.0513-4870.2022-0199

正文

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肿瘤免疫治疗显著改善了肿瘤患者的生存, 将肿瘤治疗带入了另一个崭新的时代, 其中程序性死亡受体1 (programmed cell death 1, PD-1) 及程序性死亡配体1 (programmed death ligand-1, PD-L1) 免疫检查点抑制是目前临床上应用最广泛的肿瘤免疫治疗手段之一^[1], 癌症免疫治疗现已成为对抗肿瘤疾病新的革命性策略^[2]。目前, 国外公司研发的多款PD-1/PD-L1单抗药物被应用于临床, 如nivolumab、pembrolizumab和atezolizumab等, 国内也有多款PD-1/PD-L1单抗药物进入临床应用, 如特瑞普利单抗、信迪利单抗、卡瑞丽珠单抗、舒格利单抗等。总体而言, 全球癌症免疫治疗方面取得了突破性进展。

但对大多数患者免疫检查点药物仍存在客观响应率低的问题, 其响应率仅有20%~30%^[3], 且部分患者在最初病情获得缓解之后, 随着治疗时间的推移会对疗法产生耐药性。因此应答率低、易产生耐药是肿瘤免疫治疗临床深入应用的关键瓶颈^[4]。如何增强肿瘤免疫检查点抑制剂疗效、减少免疫逃逸已经成为肿瘤治疗领域的热点问题。不少研究表明, 免疫抑制型肿瘤微环境(tumor microenvironment, TME) 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^[5]。因此, 调节肿瘤免疫微环境可能是提高免疫治疗应答率的关键之一。

在肿瘤微环境中, 高水平胞外腺苷(extracellular adenosine, eADO) 的积累对免疫应答的抑制作用受到人们越来越多的关注。这些腺苷通过腺苷受体调控肿瘤免疫反应, 腺苷-A_2A腺苷受体(A_2A adenosine receptor, A_2AR) 免疫抑制通路可以部分解释当前“冷肿瘤”形成的原因^[6]。靶向腺苷-A_2AR通路可增加免疫浸润, 增强免疫细胞功能, 将“冷肿瘤”部分逆转为“热肿瘤”, 以提高当前免疫治疗的疗效^[7]。通过靶向腺苷受体来逆转肿瘤微环境障碍, 从而提升免疫治疗效果的治疗手段越来越受到人们的关注。虽然目前还没有靶向腺苷受体的抗肿瘤药物上市, 但是有不少制药公司的腺苷受体抑制剂已经在临床试验中显示良好的效果, 有望为癌症的免疫治疗带来新的突破。因此, 本文综述了导致胞外腺苷在肿瘤微环境中积累的分子途径及A_2AR激活对肿瘤微环境中免疫细胞和肿瘤细胞的影响, 总结了A_2AR在不同癌种中的表达情况和目前靶向A_2AR的临床药物和用药策略, 讨论了靶向A_2AR可能带来的潜在不良影响, 并展望了靶向A_2AR的治疗前景。

1 腺苷在肿瘤微环境中的异常积累

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肿瘤微环境有着高度的可塑性, 在癌症发展过程中, 肿瘤代谢模式的转变也会通过代谢产物来重塑微环境, 从而为肿瘤的生长、增殖、耐药提供有利条件。

1.1 肿瘤微环境中腺苷异常积累的机制

肿瘤微环境中高水平的eADO可导致免疫抑制。正常生理条件下, 胞外腺嘌呤核苷三磷酸(extracellular adenosine triphosphate, eATP) 和eADO浓度均保持在纳摩尔范围内^{[8, 9]}, 但在由缺氧、营养缺乏、炎症等因素引发细胞死亡或细胞应激后, ATP在胞外空间迅速释放并达到微摩尔水平, 进而产生大量eADO。eATP在炎症环境中起到促炎作用, 促进免疫反应, 其水解产物eADO则主要防止过度的炎症反应, 对免疫有明显的抑制作用。胞外核苷三磷酸二磷酸水解酶-1 (ectonucleoside triphosphate diphosphohydrolase-1, CD39)、胞外5'-核苷酸酶(ectonucleoside 5'-nucleotidase, CD73) 在肿瘤微环境的细胞中高表达, 由于肿瘤微环境为局部缺氧环境, 在缺氧诱导因子1α (hypoxia-inducible factor 1α, HIF1α) 多肽介导下CD39和CD73的表达又进一步上调^[10], 加之肿瘤微环境中细胞异常更新, 导致了肿瘤微环境中腺苷产生呈指数增长。

eADO产生的经典途径是eATP被胞外CD39和CD73通过级联反应顺序去磷酸化水解为eADO^[11]。CD39是一种跨膜蛋白, 可水解eATP生成细胞外腺苷二磷酸(adenosine diphosphate, ADP) 和单磷酸腺苷(adenosine monophosphate, AMP), 之后细胞外AMP (extracellular AMP, eAMP) 再通过CD73转化为eADO。CD73是一种糖基磷脂酰肌醇锚定酶, 也可以被切割为可溶解的形式分泌在胞外。eAMP的浓度进一步受到分泌的或膜相关形式的腺苷酸激酶(ectonucleoside-adenosine kinase, ecto-AK) 和核苷酸二磷酸激酶(ectonucleoside-nucleotide diphosphate kinase, ecto-NDPK) 的调节, 这些激酶使eAMP磷酸化产生eATP。eADO的产生还包括其他非经典途径, 如环状ADP核糖水解酶(cyclic ADP ribose hydrolase, CD38) 以NAD⁺为底物生成ADP-核糖(ADP-ribosylation, ADPR), 然后外核苷酸焦磷酸酶-磷酸二酯酶1 (ectonucleoside-nucleotide pyrophosphatase/phosphodiesterase 1, CD203a) 将其加工成eAMP, 产生的eAMP再通过CD73水解为eADO。此外, 其他膜结合磷酸酶, 如组织特异或非特异性碱性磷酸酶也可以将eAMP水解为eADO。

1.2 不同腺苷受体类型及其调控机制

腺苷特异性受体包括A₁、A_2A、A_2B和A₃等4种不同的G蛋白偶联受体, 其对ADO的亲和力Ki分别为100 nmol·L^-1、310 nmol·L^-1、15 μmol·L^-1和290 nmol·L^-1^[12]。A_2AR广泛分布于脾脏、胸腺、血小板、白细胞、嗅球和苍白纹状体的氨基丁酸能神经元中。在肿瘤微环境中, A_2AR主要参与eADO介导的免疫抑制(图 1), 其通过与Gs/Golf蛋白配对激活腺苷酸环化酶(adenylate cyclase, AC) 生成环磷酸腺苷(cyclic adenosine monophosphate, cAMP), 进而激活cAMP依赖性蛋白激酶(protein kinase A, PKA) 并激活多种离子通道、受体、cAMP反应元件结合蛋白(cAMP-response element binding protein, CREB) 等^[13]。目前, 各大制药公司的腺苷受体抑制剂也主要靶向A_2AR, 因此本文重点讨论A_2AR在肿瘤免疫治疗中的作用。

1.3 腺苷受体A_2AR在不同癌种中的表达情况

多数实体瘤具有缺氧和炎症的性质, 与相应的非肿瘤组织相比, A_2AR在许多类型肿瘤的TME中高表达(图 2), 可以预计靶向A_2AR对A_2AR过表达类型的肿瘤可能有较好的疗效, 尤其是在弥漫大B细胞淋巴瘤、胸腺瘤、腱鞘巨细胞瘤等肿瘤中。但是A_2AR的表达量不一定能代表预后情况, mRNA水平的差异并不一定意味着与蛋白表达水平差异相关, 且肿瘤样本的基因表达谱分析也并不能正确地反映出eADO的免疫抑制作用及肿瘤对治疗的反应。

2 A_2AR在肿瘤微环境中的作用及对免疫应答的调控

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在肿瘤微环境中, 激活腺苷-A_2AR信号通路可抑制免疫细胞的成熟和效应功能, 促进免疫细胞向免疫抑制型表型转化, 导致免疫逃逸, 同时, 其也可以促进上皮间质转化(epithelial-mesenchymal transition, EMT), 促进肿瘤进展和转移。

2.1 A_2AR对免疫细胞的调控和机制

在肿瘤微环境中, 高浓度的eADO会与免疫细胞膜表面的A_2AR结合产生免疫抑制信号, 从而抑制T细胞、B细胞、NK细胞等免疫细胞的增殖、成熟和效应功能, 导致机体的免疫损伤和肿瘤细胞增殖。

A_2AR在免疫细胞上普遍高表达, 其能够参与调节体内各个阶段的免疫反应^[14]。Sitkovsky课题组^[11]里程碑式的研究表明, 激活A_2AR-cAMP信号通路所引起的免疫抑制在过度炎症期间对保护正常组织有关键作用。

A_2AR激活会抑制T细胞激活、增殖、分化和细胞因子分泌等生理过程^[15], 包括通过抑制多种丝裂原活化蛋白激酶(mitogen-activated protein kinases, MAPK), 如细胞外调节蛋白激酶(extracellular regulated protein kinases, ERK1)、c-Jun氨基末端激酶(c-Jun N-terminal kinase, JNK)^[16]及蛋白激酶C (protein kinase C, PKC) 的活性, 抑制CREB介导的核因子κB (nuclear factor kappa-B, NF-κB)^[9]和活化型T细胞的核因子(nuclear factor of activated T-cells, NF-AT) 产生^[17]。除此之外, A_2AR激活还通过上调转化生长因子-β (transforming growth factor β, TGF-β) 和叉头样转录因子P3 (forkhead box protein P3, FOXP3) 的表达^[18] (图 3), 抑制Th1和Th17效应细胞的产生并促进调节性T细胞的分化和增殖^[19], 进一步抑制免疫反应。值得一提的是, A_2AR激动剂不能预防淋巴细胞激活基因-3 (lymphocyte activation gene 3, LAG-3) 缺失克隆型T细胞的自身免疫, 这意味着LAG-3在腺苷诱导的外周耐受中可能起着重要作用^[20]。

T细胞抗原受体(T cell receptor, TCR) 信号传导会上调A_2AR的表达^[16], 而A_2AR的激活会干扰TCR近端信号, 干扰CD3^[21]、CD28^[22]共活化信号和白介素-2 (interleukin-2, IL-2) 受体信号的传导, 抑制电导钙激活性钾离子通道(intermediate-conductance Ca²⁺-activated K⁺ channel, KCa3.1) 活性, 进一步抑制T细胞增殖及其功能^[23]。Zeta链缔合蛋白(zeta chain of T cell receptor associated protein kinase 70, ZAP70) 是参与T细胞信号转导途径的特异性非受体型酪氨酸激酶蛋白, 在响应TCR信号转导诱导T细胞激活中发挥关键作用。A_2AR与T细胞结合激活AC, 从而产生大量胞内cAMP, 进而导致PKA激活和C-Src酪氨酸激酶(C-Src tyrosine kinase, CSK) 磷酸化, 磷酸化的CSK使淋巴细胞特异性蛋白酪氨酸激酶(lymphocyte specific protein tyrosine kinase, LCK) 失活^[24], 最终抑制ZAP70的活化。LCK驱动的磷酸化靶点还包括CD28、细胞毒性T淋巴细胞相关蛋白4 (cytotoxic T-lymphocyte-associated protein 4, CTLA-4) 及免疫细胞特异性衔接蛋白T细胞活化连接蛋白(linker for activation of T cell, LAT) 和SLP-76等。A_2AR活化后LCK的失活也使得CD28介导的T细胞共活化被抑制^[25]。除了抑制T细胞活化的第一及第二信号, A_2AR活化还可以抑制细胞因子受体信号, A_2AR激活cAMP-PKA依赖性信号通路, 进一步激活Src同源2含蛋白质酪氨酸磷酸酶2 (Src homology 2 containing protein tyrosine phosphatase 2, SHP-2) 并导致下游的信号传导及转录激活蛋白5 (signal transducer and activator of transcription 5, STAT5) 去磷酸化, 从而阻断T细胞中IL-2受体信号^[26] (图 3)。

除了T细胞外, A_2AR也在其他免疫细胞上表达参与免疫抑制(图 4)。在肥大细胞中, A_2AR与腺苷结合阻断KCa3.1钾通道的活性, 减少了IgE和Ca3介导的脱颗粒, 并抑制肥大细胞趋化性^[27]。巨噬细胞中A_2AR的激活通过促进cAMP、磷脂酰肌醇激酶(phosphoinositide 3-kinase, PI3K) 及PKC信号, 诱导肿瘤巨噬细胞M2型极化^[28]。巨噬细胞起吞噬作用时会摄取、降解并最终呈递源自微粒抗原的肽, 当小颗粒被IgG包被时, IgG抗体分子的Fc区与在巨噬细胞质膜上表达的Fc受体结合并触发吞噬反应, A_2AR特异性激活能够抑制Fcγ受体介导的巨噬细胞的吞噬作用^[29]。此外, 肿瘤活化的巨噬细胞释放的自分泌粒细胞-巨噬细胞集落活化因子能够增强巨噬细胞上A_2AR的表达, 并与腺苷协同作用通过A_2AR-PI3K/AKT和MEK/ERK途径调节人肝脏肿瘤中的巨噬细胞增殖^[30]。A_2AR的特异性激活也可以上调B16F10黑色素瘤的巨噬细胞浸润并调节巨噬细胞极化^[31]。A_2AR介导的cAMP-PKA信号激活会诱导多种免疫抑制, 包括抑制中性粒细胞的吞噬、氧化活性(活性氧, reactive oxygen species, ROS生成)、趋化性和黏附^{[32, 33]}, 阻断B细胞的抗原受体和Toll样受体4信号, 抑制B细胞增殖^[34], 阻碍NK细胞的成熟、增殖和细胞溶解活性^[35]。

2.2 A_2AR对肿瘤细胞的调控和机制

eADO与A_2AR结合不仅具有免疫抑制作用, 还能以肿瘤细胞自主的方式促进肿瘤细胞的进展、侵袭和转移。A_2AR通常通过激活PI3K/AKT/mTOR信号传导促进肿瘤进展和转移^[21]。在肝癌的临床前模型中, eADO与A_2AR结合激活Ras相关蛋白1 (Ras-associated protein 1, Rap1) 募集PI3K催化亚基P110β到质膜并触发3-磷酸磷脂酰肌醇(phosphatidylinositol 3-phosphate, PIP3) 产生, 从而促进肝细胞癌细胞的丝氨酸/苏氨酸激酶(AKT) 磷酸化, 促进肝细胞癌的发展和转移^[36]。在胃癌的临床前模型中, 胃癌细胞上的A_2AR表达促进了癌细胞转移^[21]。在乳腺癌的临床前模型中, A_2AR通过激活血管内皮生长因子和碱性成纤维细胞生长因子参与肿瘤血管生成^[37], 促进乳腺癌细胞生长、迁移和骨转移^{[38, 39]}。此外, 在CD73高表达的三阴性乳腺癌中, A_2AR的激活可抑制多柔比星等蒽环类药物的疗效, 导致患者有更差的预后, 对于此类癌症患者, 靶向A_2AR可以在一定程度上拮抗化疗耐药^[40]。肿瘤免疫抑制也是白血病治疗失败和复发的主要原因, 研究发现在白血病细胞密集定植的缺氧淋巴细胞生态位中, eADO大量积累且其下游信号转导被上调, 腺苷-A_2AR信号激活促进慢性淋巴细胞白血病的免疫耐受, 因此阻断该通路具有较高的临床意义^[41]。

EMT与肿瘤的发生、侵袭、转移和对其治疗策略的选择密切相关^[42]。在肝细胞癌模型中, A_2AR的激活促进EMT和癌症干细胞特征^[36]。TGF-β是诱导EMT最重要的因子, Yang课题组^[43]发现腺苷-A_2AR通路相关特征基因与人类癌症中的TGF-β基因表达密切相关。

2.3 A_2AR在免疫治疗耐受中的作用

癌症免疫治疗可在不同类型癌症患者体内持续激发抗肿瘤免疫应答, 部分患者即使初期对免疫治疗药物有响应, 一段时间后也会产生耐药, 这是目前免疫治疗面临的重要临床挑战之一。免疫疗法产生耐药的原因主要包括: 肿瘤抗原、人类白细胞抗原(human leukocyte antigen, HLA) 的表达缺失; 抗原加工机制的改变; 信号通路(MAPK、PI3K、WNT、IFN) 的突变; 免疫抑制细胞群(Tregs、Ⅱ型巨噬细胞) 的增加和肿瘤微环境中细胞因子、代谢物(腺苷、集落刺激因子1、TGF-β) 的释放等^[44]。腺苷是肿瘤微环境中重要的免疫抑制代谢产物, 腺苷激活A_2AR可抑制T细胞增殖、成熟及其功能, 靶向A_2AR是克服免疫治疗耐药的策略之一^[45]。Darcy团队^[46]的研究证明, A_2AR的药理学和基因抑制均增强了嵌合抗原受体T细胞(chimeric antigen receptor T-cell, CAR-T) 在两种不同的乳腺癌小鼠模型中的功效。Smyth课题组^[47]的研究也证明A_2AR抑制剂与CD73抑制剂的联用可通过增加免疫细胞与Fc受体的结合从而限制肿瘤的发生、发展。在临床中, 对于肾癌^[48]、前列腺癌^[49]及非小细胞肺癌^[50], A_2AR拮抗剂与PD-L1抑制剂联用可减少耐药发生, 显著增加免疫细胞浸润, 诱导持久的抗肿瘤免疫反应。由此可见, 靶向腺苷-A_2AR通路的免疫治疗将为克服免疫治疗耐药带来新的希望。

3 A_2AR抑制剂研发进展

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目前, 大多数报道的检查点抑制剂是单克隆抗体^[51], 此类药物多数昂贵且给药方案耗时。更重要的是, 一些与单克隆抗体有关的免疫不良事件常被报道, 但现在仍然缺乏有效的解决方案。与生物制剂相比, 免疫调节类小分子药物具有更高的口服生物利用度、更好的肿瘤微环境通透性, 并且由于小分子的生物利用度更易控制, 从而可以避免一些免疫相关的不良事件, 此外, 较低的生产和管理成本也能够更好地满足患者的需求。随着腺苷受体作用机制的不断解析, 越来越多的制药公司投入到A_2AR拮抗剂的研发之中, 有些药物分子已经在临床试验中取得突破性进展, 展示良好的治疗效果(表 1)。

3.1 Ciforadenant (CPI-444)

用CPI-444阻断A_2AR可在体外恢复被腺苷类似物抑制的T细胞信号。在多个同源小鼠肿瘤模型中, CPI-444治疗可以剂量依赖性地抑制肿瘤生长。在接受CPI-444与PD-L1单抗或CTLA-4单抗联合治疗的小鼠中, 多达90%小鼠的肿瘤消除, 这包括对PD-L1单抗或CTLA-4单抗单独治疗反应不明显的模型恢复免疫应答的情况^[52]。新型A_2AR拮抗剂CPI-444能够在癌症的检查点治疗和获得性细胞疗法(adoptive cell transfer therapy, ACT) 模型中显著增强免疫反应^[53]。一项临床研究中33例接受ciforadenant单药治疗的肾细胞癌患者中有1例(3%)、35例接受联合治疗的肾细胞癌患者中有4例(11%) 出现了RECIST标准的部分反应。另外24%的患者虽出现了肿瘤消退, 但不符合RECIST标准中关于部分反应的标准。接受CPI-444单药治疗的患者中有17%, 联合治疗组中有39%的患者在连续至少6个月内疾病进展得到了控制; CPI-444单药治疗和联合治疗的中位无进展生存期分别为4.1和5个月。联合治疗组在25个月内的估计总生存期(overall survival, OS) 率超过90%, 单药治疗组在16个月内的OS率超过69%^{[48, 54]}。其中超过72%的患者既往对抗PD-1单抗或PD-L1抗体治疗具有耐药性, 单药治疗组和联合治疗组自上次服用抗PD-1单抗或PD-L1抗体后的中位时间分别为3.1个月(1.2~70.4个月) 和1.7个月(0.9~23.6个月)。不良事件主要包括疲劳、瘙痒和食欲下降, 3级或4级不良事件较少见。在接受治疗期间, 没有发生任何与治疗或疾病相关的死亡。

3.2 AZD4635

使用AZD4635抑制A_2AR可通过内部机制恢复T细胞功能及CD103⁺ DCs的肿瘤抗原交叉呈递产生的抗肿瘤免疫^[55]。一项临床研究中, 15例晚期恶性肿瘤患者接受AZD4635单药治疗, 23例患者接受AZD4635和durvalumab联合治疗, 所有受试者之前至少采用过1个治疗方案(中位数为3个), AZD4635在单药治疗或联合治疗中的最大耐受剂量均为每日口服100 mg, 在给药间隔时间内给予最大耐受剂量时, AZD4635的平均血药浓度高于体外的IC₅₀, 在每日两次给予125 mg剂量时出现两种剂量限制毒性(DLT; 3级恶心和2级腹痛), 并且在每日一次给予75 mg联合durvalumab时出现一次DLT (2级恶心+ 2级疲劳)。应用AZD4635单药治疗或联合durvalumab治疗的转移性去势抵抗性前列腺癌患者中有8例受试者符合RECIST评估标准, 此外, 在4例RECIST不可评估的受试者中, 有1例通过AZD4635单药治疗后可观察到前列腺特异性抗原持续下降 > 99%^[50]。

3.3 Taminadenant (PBF-509/NIR178)

在体外, PBF-509对A_2AR具有高度特异性, 并抑制A_2AR功能。在小鼠模型中, 与对照组相比, 经PBF-509治疗后肺部肿瘤转移减少。先前的体外研究显示, 当PBF-509与PD-1单抗或PD-L1单抗药物联合使用时, 人的肿瘤浸润性淋巴细胞的反应性增加^[56]。一项Ⅰ/Ⅱ期临床研究(NCT02403193) 评估了PBF-509在既往接受过治疗的晚期非小细胞肺癌患者中的疗效。24例患者接受了PBF-509单药治疗, 研究性治疗导致的最常见的不良事件(≥ 20%) 包括恶心、疲劳、呼吸困难、呕吐、胸痛、胃食管反流病、贫血、腹泻、厌食、全身肌肉无力和咳嗽。在每日两次给予640 mg剂量时出现DLT (3级恶心)。此外, 无论PD-L1表达水平如何, 在接受过免疫治疗和未接受过免疫治疗的患者中均观察到临床获益^[49]。

3.4 AB928

AB928对A_2AR和A_2BR具有相似的亲和力(Ki分别为1.4和2 nmol·L^-1)^[57]。AB928已被证明可减缓肿瘤生长, 无论是单独使用还是联合抗PD-1药物^{[58, 59]}或化疗^[60]。目前, AB928是临床上唯一的A_2A和A_2B双靶点抑制剂。在一项Ⅰ期临床研究中, 与AB928相关的最常见的治疗相关不良事件是腹痛、恶心、头晕、头痛、腹胀和便秘。尽管AB928在各种癌症小鼠模型中显示出了抗肿瘤活性, 但仍缺乏支持联合抑制A_2A和A_2B受体比单独抑制A_2A受体更有优势的临床前数据(NCT03629756、NCT03720678和NCT03719326)。截至2022年2月, 目前已有3项肿瘤治疗临床试验完成, 但是其肿瘤治疗的临床数据还未被披露。

3.5 PBF-999

PBF-999是一种A_2AR/PDE-10A双重拮抗剂。抑制PDE-10A可抑制环磷酸鸟苷(cyclic guanosine monophosphate, cGMP) 降解, cGMP水平的增加可抑制肿瘤增殖并诱导细胞凋亡, 因此同时拮抗A_2AR和PDE-10A可能会发挥协同抗肿瘤作用。一项针对可活检实体瘤患者的Ⅰ期剂量递增研究正在进行中。据报道, PBF-999在Ⅰ期临床试验的剂量在范围从20~120 mg组中是安全且耐受性良好的^[61]。

3.6 Inupadenant (EOS100850)

EOS100850是一种非脑穿透性A_2AR拮抗剂, 在体外具有高度选择性, 在高腺苷浓度的环境中仍保持强抑制作用^[62]。EOS100850与CTLA-4单抗联合使用可增加CD8⁺ T细胞的数量并激活浸润肿瘤微环境的巨噬细胞。在EMT-6小鼠模型中, 与CTLA-4单抗单药治疗相比, EOS100850与CTLA-4单抗联合使用具有更高的肿瘤生长抑制率, 且可以诱导免疫记忆^[63]。

目前EOS100850已进入Ⅰ期临床试验。研究的第一阶段是评估EOS100850的安全性和耐受性, 测试的剂量水平为每天20和40 mg, 以及每天2次40、80和160 mg, 结果显示所有剂量水平耐受性良好, 没有3级或4级相关不良事件, 并且EOS100850在7例患者中证明了单药治疗具有疗效, 在接受过免疫检查点抑制剂治疗的难治性黑色素瘤患者和化疗耐药前列腺癌患者中观察到持续的免疫反应(NCT05117177)。

3.7 EXS21546

EXS21546是Evotec和Exscientia在2018年公布的一种新的非脑穿透性A_2AR/CD73拮抗剂, 它是第一个进入临床的AI设计的肿瘤免疫新药。EXS21546降低了由腺苷受体激动剂NECA活化的HEK细胞产生的cAMP, 并显示出在体外恢复原代人CD3⁺ T淋巴细胞中产生的IL-2效力^[64]。

随后, 在2021年公布了EXS21546离体治疗在原发性胰腺癌和肺癌细胞的临床前数据, 结果表明在高浓度的腺苷类似物存在下EXS21546能够降低癌细胞的存活, 并且可以诱导CD8⁺ T淋巴细胞的部分增殖^[65]。目前, 正在开展一项临床试验(NCT04727138), 旨在评估单次给药和多次递增剂量给药的安全性、耐受性和药代动力学。

3.8 CS3005

CS3005是由基石药业开发的A_2AR拮抗剂, 目前正在开展一项临床试验(NCT04233060), 主要是测试其在临床上的安全性和初步活性。招募对象为组织学证实为晚期实体瘤的受试者, CS3005将每天两次口服给药, 试验期限为两年, 两年内病情进展或产生不可接受的不良反应将停止试验, 预计2022年将完成Ⅰ期试验。

3.9 SHR5126

SHR5126由恒瑞制药公司开发, 并于2020年2月获得药品审评中心(CDE) 临床试验批准, 具体适应症待临床试验确定, 拟用于晚期实体廇患者的治疗。其前期实验表明, 作为一种腺苷受体A_2AR抑制剂, SHR5126可通过与腺苷竞争性结合A_2AR, 使免疫细胞保持免疫活性, 从而实现对肿瘤细胞的杀伤。

3.10 Preladenant (MK-3814A)

MK-3814A是一种首先用于治疗帕金森病的口服A_2AR拮抗剂^[66]。MK-3814A曾进行过晚期实体瘤的Ⅰ期临床研究, 但是由于数据不支持研究终点, 该试验被提前终止。

4 靶向A_2AR的治疗策略

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目前, 多种A_2AR拮抗剂已在临床前及临床模型中进行尝试, 其通常与免疫检查点抑制剂、化疗和ACT的药物联用来改善抗癌作用。

除了产生细胞外腺苷, CD73在肿瘤细胞或内皮细胞上表达对肿瘤细胞黏附、外渗和转移也至关重要, 同时靶向A_2AR与CD73的联合治疗也是一个非常有前景的策略。Young等^[35]对同时缺乏A_2AR和CD73的双基因缺陷(DKO) 小鼠的研究表明, 与单基因缺陷小鼠相比, DKO小鼠对抗PD-1耐药、BRAF突变的SM1WT1黑色素瘤肿瘤模型表现出更大的肿瘤排斥反应, 联合阻断A_2AR和CD73限制了肿瘤的增殖和转移。此外, CD39在免疫细胞、肿瘤相关内皮细胞及肿瘤细胞上的表达也与免疫抑制、肿瘤生长和转移有关。A_2AR拮抗剂与CD39抑制剂联用可提升肿瘤微环境中ATP的积累, 促进肿瘤细胞的死亡, 进而增强免疫系统的攻击能力^[67]。

A_2AR拮抗剂通常与免疫检查点抑制剂联合使用, 在抗原激活的T细胞上A_2AR过表达, 即使阻断PD-(L)1减少T细胞的程序性死亡, 肿瘤微环境中累积的大量腺苷也会导致T细胞无法正常发挥功能, 所以同时阻断这两种分子有十分重要的临床和科研价值。Waickman等^[68]率先研究了A_2AR拮抗剂联合共抑制分子的作用, 在他们最初的报告中, 其证明了在EL4胸腺瘤肿瘤模型中, 使用B7-DC/Fc融合蛋白联合A_2AR拮抗剂共同刺激T细胞, 可显著减缓肿瘤生长。Beavis等^[69]的研究还表明, 与单药治疗相比, A_2AR和PD-1的联合阻断增加了肿瘤中干扰素-γ (interferon-γ, IFN-γ) 的产生。Iannone等^[70]也证明了在小鼠B16F10黑色素瘤模型中同时阻断A_2AR和CTLA-4的治疗效果明显优于单药治疗, 且临床前研究表明, A_2AR拮抗剂和免疫检查点制剂联用可能对表达高水平CD73的肿瘤患者更有效果^[71]。

靶向A_2AR也被证明与化疗有协同作用。某些化疗药物可以诱导免疫原性的细胞死亡, 触发抗肿瘤免疫反应, 这一过程被证明与ATP释放增加有关, 尽管ATP积累是促炎的, 但在肿瘤微环境中高表达的CD39和CD73可以将其分解成腺苷, 形成免疫抑制环境。有研究表明, 靶向A_2AR可以显著提高小鼠模型中蒽环类药物的疗效^[72]。

最近的临床前研究表明, 将CAR-T细胞治疗与A_2AR阻断相结合也具有指导意义。Beavis等^[46]的研究表明, 与对照小鼠相比, A_2AR敲除小鼠的CAR-T细胞表现出更高的活性, 靶向A_2AR会增强体内外CD8 CAR-T细胞的细胞因子产生。

5 靶向A_2AR的潜在不良反应和应对策略

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A_2AR广泛分布于哺乳动物组织中^[73], 具有重要的生理功能^[74]。抑制A_2AR可引起多种疾病, 包括动脉硬化、免疫衰退、糖尿病、哮喘、溃疡、多动症、认知功能障碍等^{[75, 76]}。

腺苷与小动脉血管平滑肌细胞上的A_2AR结合激活K (V) 和K (ATP) 通道^[77]介导血管舒张, 因此在临床中广泛应用于诱导冠状动脉舒张^[78]。然而, 由于腺苷受体不是心肌组织所特有的, 在治疗时会诱发相关不良反应, 如支气管痉挛、呼吸困难或房室传导阻滞^[79]。腺苷与A_2AR结合主要起抗炎作用^[7], 炎症主要是由血管舒张和渗漏引起的, 几乎所有参与炎症过程的细胞都表达A_2AR。在肾脏和小肠^[80]中, 多种细胞类型的A_2AR信号共同调节结肠炎^[81], 小鼠的A_2AR基因缺失增加了其结肠炎的易感性^[82]。在肺中, A_2AR的激活可以抑制卵清蛋白致敏的棕色挪威大鼠暴露于过敏原中所引起的早期和晚期炎症反应^[83]。

A_2AR与骨代谢密切相关, 其激动剂可抑制破骨细胞功能, 减少骨肉瘤患者的骨质破坏。此外, A_2AR激动剂可以募集骨髓间充质干细胞并激活成骨细胞, 而缺乏A_2AR会导致骨质流失^[19]。A_2AR拮抗剂能够抑制骨愈合过程中血管生成和巨噬细胞分泌外泌体, 从而减缓骨折后的恢复过程^[84]。A_2AR基因敲除小鼠将会自发性产生骨关节炎, 并且腺苷通路水平下降也被证实与人类骨关节炎有关^[85]。

A_2AR在大脑中尤其在纹状体、颈动脉体和海马神经末梢中高表达, 在神经元发育、神经保护和稳态功能中发挥重要作用^[86]。A_2AR的表达情况与学习和记忆过程密切相关, 缺失或过表达均会引起不同的损伤^[87]。A_2AR可与多巴胺D2受体形成异质共聚物, 从而拮抗多巴胺D2受体的信号传导, 调节运动^[88], 各种研究表明A_2AR与帕金森病、亨廷顿病等退行性疾病密切相关^{[89, 90]}。大多数A_2AR拮抗剂都是最初为帕金森病开发的竞争性抑制剂, 因此, 它们大部分可以穿透血脑屏障, 甚至提高其通透性^[91], 这可能会对大脑造成损伤。

如何减少靶向A_2AR的潜在风险也正在研究中, 脂质体或纳米颗粒^[92]的开发及基因编辑可更有效地靶向肿瘤微环境中的A_2AR, 以减少可能由A_2AR广泛表达引起的全身毒性。Laura的团队^[93]开发了脂质纳米颗粒, 递送A_2AR基因沉默RNA, 以敲除T细胞中的A_2AR, 并成功抑制在头颈部鳞状细胞癌中腺苷对记忆T细胞趋化性的抑制作用, 最终有助于增加T细胞浸润到肿瘤中。目前, 靶向腺苷在癌症治疗中的局限之处在于患者的肿瘤需要表现出缺氧和富含腺苷的肿瘤微环境的特点, 并表现出足够数量的肿瘤反应性T细胞^[94]。以CRISPR/Cas9介导的CAR-T细胞中A_2AR缺失显著抵抗腺苷介导的转录变化, 导致包括IFN-γ和肿瘤坏死因子在内的细胞因子的产生增加, 因此改善了CAR-T细胞的临床应用^[95]。

6 靶向A_2AR的治疗前景展望

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在肿瘤微环境中, 肿瘤和免疫细胞会经历明显的代谢重编程, 腺苷作为肿瘤微环境中大量存在的免疫抑制性代谢产物可与A_2AR结合, 促进肿瘤发生发展。

目前肿瘤微环境调节剂的研究如火如荼, A_2AR拮抗剂作为一种肿瘤免疫微环境调节剂, 其抗肿瘤的作用主要通过与腺苷竞争性地结合A_2AR来实现, 作为免疫治疗增强剂可大幅增加当前癌症免疫治疗的疗效, 虽然其激动剂与拮抗剂结合模式的区别尚未可知。

临床前和临床研究表明, 靶向腺苷-A_2AR通路增加免疫浸润, 削弱免疫抑制, 将对免疫治疗不敏感的“冷肿瘤”部分逆转为“热肿瘤”。在临床试验中, A_2AR拮抗剂已与CD39、CD7、PD-(L)1、CTLA-4等抑制剂联用, 均表达出比单药治疗更好的疗效, 未来可能与更多免疫检查点药物联用来提升肿瘤免疫治疗的应答率和可及性。此外, 胞外腺苷的产生与肿瘤微环境内缺氧和细胞高速更新密不可分, 所以靶向A_2AR和可以促进缺氧和细胞死亡的放、化疗联用也可能会在临床上取得更好的疗效。因为A_2AR在心脏、大脑、神经等器官、组织中也有较高表达, 因此减弱靶向全身A_2AR引起的潜在风险也应该被关注。总体而言, 通过靶向腺苷受体来逆转肿瘤微环境障碍从而提升免疫治疗的效果, 越来越受到科学界和药物产业界的关注。虽然目前还没有靶向A_2AR腺苷受体的抗肿瘤药物上市, 但是一些腺苷受体抑制剂已经在临床试验中显示良好的效果, 有望未来为癌症的免疫治疗带来新的突破。

作者贡献: 张芷菁、张启怡、金祖翼、朱凯负责文献调研和文章撰写; 丁文、张小雷确定文章思路及文章审阅。

利益冲突: 本文作者均声明无利益冲突。

基金

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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)
广州市科技计划项目-基础与应用基础研究项目(202103000097)
吉林省科技发展计划项目(20200404105YY)
吉林省科技发展计划项目(20210204055YY)

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2022年第57卷第9期

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doi: 10.16438/j.0513-4870.2022-0199

接收时间：2022-02-16
首发时间：2025-12-24
出版时间：2022-09-12

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收稿日期：2022-02-16
修回日期：2022-03-17

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)

广州市科技计划项目-基础与应用基础研究项目(202103000097)

吉林省科技发展计划项目(20200404105YY)

吉林省科技发展计划项目(20210204055YY)

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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

通讯作者:

*丁文, dingw8@mail2.sysu.edu.cn;

张小雷, Tel: 86-20-39943021, E-mail: zhangxlei5@mail.sysu.edu.cn

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2种不同金属材料的力学参数

科 Family	属数 Number of genus	种数 Number of species	占总种数比例 Percentage of total species (%)	属 Genus	种数 Number of species	占总种数比例 Percentage of total species (%)
鹅膏菌科Amanitaceae	2	11	5.26	鹅膏菌属 Amanita	10	4.78
小菇科 Mycenaceae	2	12	5.74	丝盖伞属 Inocybe	5	2.39
多孔菌科 Polyporaceae	8	14	6.70	蜡蘑属 Laccaria	5	2.39
红菇科 Russulaceae	3	23	11.00	小皮伞属 Marasmius	6	2.87
				小菇属 Mycena	11	5.26
				光柄菇属 Pluteus	5	2.39
				红菇属 Russula	17	8.13
				栓菌属 Trametes	5	2.39

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RefWorks
TxT

Drug name	Indication	Sponsor	Phase	Intervention/treatment	Clinical trial identifier
Ciforadenant (CPI-444)	Multiple myeloma	Corvus	Ib	+ Daratumumab	NCT04280328
NSCLC/RCC/CRC/TNBC/cervical cancer/OC/PC/endometrial cancer/sarcoma/HNSCC/bladder cancer/mCRPC/non-hodgkin lymphoma	Corvus	Ⅰ/Ⅰb	+ CPI-006	NCT03454451
RCC/mCRPC	Corvus	Ⅰ/Ⅰb	Single agent/+ atezolizumab	NCT02655822
NSCLC	Corvus	Ⅰb/Ⅱ	+ atezolizumab	NCT03337698
AZD4635	Advanced solid malignancies	AstraZeneca	Ⅰ	Single agent	NCT03980821
Advanced solid malignancies/NSCLC/mCRPC/CRC	AstraZeneca	Ⅰ	Single agent/+ durvalumab/enzalutamide/abiraterone acetate/durvalumab + oleclumab/docetaxel	NCT02740985
Prostate cancer/mCRPC	AstraZeneca	Ⅱ	+ Durvalumab/+ oleclumab/+ durvalumab + oleclumab	NCT04089553
mCRPC	AstraZeneca	Ⅱ	+ Durvalumab/+ durvalumab + cabazitaxel	NCT04495179
Carcinoma/NSCLC	AstraZeneca	Ⅰb/Ⅱ	+ MEDI9447	NCT03381274
PBF-509 (NIR178)	NSCLC	Palobiofarma	Ⅰ/Ⅰb	Single agent/+ PDR001	NCT02403193
NSCLC/TNBC/PDAC/MSS/OC/RCC/mCPRC	Novartis	Ⅰ	+ NZV930/PDR001	NCT03549000
Solid tumors	Novartis	Ⅰ	+ KAZ954	NCT04237649
TNBC	Novartis	Ⅰ	+ PDR001/LAG525	NCT03742349
NSCLC/RCC/pancreatic cancer/urothelial cancer/head and neck cancer/DLBCL/MSS/ TNBC/melanoma	Novartis	Ⅱ	+ PDR001	NCT03207867
RCC	Novartis	Ⅰ/Ⅰb	+ PDR001+ DFF332	NCT04895748
Etrumadenant(AB928)	Metastatic castration-resistant prostate cancer/prostate cancer	Surface Oncology	Ⅱ	+ SRF617 + zimberelimab	NCT05177770
NSCLC/HNSCC/breast cancer/CRC/melanoma/bladder cancer/OC/endometrial cancer/merkel cell carcinoma/gastroesophageal cancer/renal cell carcinoma/CRPC	Arcus	Ⅰ	+ Zimberelimab	NCT03629756
Head and neck cancer/squamous cell carcinoma of head and neck/oral cavity squamous cell carcinoma/oral cavity cancer/oropharynx cancer/oropharynx/squamous cell carcinoma/larynx cancer/pharynx cancer/hypopharynx cancer/hypopharynx squamous cell carcinoma	Arcus	Ib	+ Concurrent cisplatin/+ radiation therapy + zimberelimab	NCT04892875
Metastatic colorectal cancer	Arcus	Ⅰb/Ⅱ	+ Zimberelimab + mFOLFOX-6 + bevacizumab/+ zimberelimab + AB680	NCT04660812
Prostatic neoplasms, castration-resistant/androgen-resistant prostatic neoplasms/castration resistant prostatic neoplasms/prostatic cancer, castration-resistant	Arcus	Ⅰb/Ⅱ	+ Zimberelimab + enzalutamide/+ trumadenant + zimberelimab + docetaxel/+ zimberelimab/+ zimberelimab + AB680/+ AB680	NCT04381832
Gastro esophageal cancer/CRC	Arcus	Ⅰ/Ⅰb	+ mFOLFOX	NCT03720678
TBNC/OC	Arcus	Ⅰ/Ⅰb	+ PLD/+ NP/+ PLD + IPI-549	NCT03719326
NSCLC metastatic/NSCLC/nonsquamous non small cell neoplasm of lung/sensitizing EGFR gene mutation	Arcus	Ⅰ/Ⅰb	+ Carboplatin + pemetrexed/+ carboplatin + pemetrexed + pembrolizumab/+ zimberelimab + carboplatin + pemetrexed	NCT03846310
NSCLC/nonsquamous NSCLC/squamous NSCLC/lung cancer	Arcus	Ⅱ	+ Domvanalimab + zimberelimab	NCT04262856
NSCLC/non-small cell carcinoma	Arcus	Ⅱ	+ Zimberelimab + domvanalimab	NCT04791839
Rectal cancer	Arcus	Ⅱ	+ FOLFOX regimen + zimberelimab	NCT05024097
Prostate adenocarcinoma	Genentech	Ⅱ	+ Atezolizumab	NCT03821246
Pancreatic adenocarcinoma	Roche	Ⅰb/Ⅱ	+ Atezolizumab + chemotherapy	NCT03193190
CRC	Roche	Ⅰb/Ⅱ	Single agent/+ atezolizumab + regorafenib	NCT03555149
Inupadenant (EOS100850)	Solid tumor	iTeos	Ⅰ/Ⅰb	Single agent/+ pembrolizumab/+ chemotherapy	NCT03873883
Solid tumor	iTeos	Ⅰ	Single agent	NCT05117177
Advanced cancer/lung cancer/head and neck cancer/melanoma	iTeos	Ⅰ/Ⅱ	Inupadenant +EOS-448/inupadenant + pembrolizumab	NCT05060432
CS3005	Advanced solid tumors	CStone	Ⅰ	Single agent	NCT04233060
EXS21546	Oncology	Exscientia	Ⅰ	Single agent	NCT04727138
PBF-999	Advanced solid tumor	Palobiofarma	Ⅰ	Single agent	NCT03786484

Drug name

Indication

Sponsor

Phase

Intervention/treatment

Clinical trial identifier

Ciforadenant (CPI-444)

Multiple myeloma

Corvus

+ Daratumumab

NCT04280328

NSCLC/RCC/CRC/TNBC/cervical cancer/OC/PC/endometrial cancer/sarcoma/HNSCC/bladder cancer/mCRPC/non-hodgkin lymphoma

Corvus

Ⅰ/Ⅰb

+ CPI-006

NCT03454451

RCC/mCRPC

Corvus

Ⅰ/Ⅰb

Single agent/+ atezolizumab

NCT02655822

NSCLC

Corvus

Ⅰb/Ⅱ

+ atezolizumab

NCT03337698

AZD4635

Advanced solid malignancies

AstraZeneca

Ⅰ

Single agent

NCT03980821

Advanced solid malignancies/NSCLC/mCRPC/CRC

AstraZeneca

Ⅰ

Single agent/+ durvalumab/enzalutamide/abiraterone acetate/durvalumab + oleclumab/docetaxel

NCT02740985

Prostate cancer/mCRPC

AstraZeneca

Ⅱ

+ Durvalumab/+ oleclumab/+ durvalumab + oleclumab

NCT04089553

mCRPC

AstraZeneca

Ⅱ

+ Durvalumab/+ durvalumab + cabazitaxel

NCT04495179

Carcinoma/NSCLC

AstraZeneca

Ⅰb/Ⅱ

+ MEDI9447

NCT03381274

PBF-509 (NIR178)

NSCLC

Palobiofarma

Ⅰ/Ⅰb

Single agent/+ PDR001

NCT02403193

NSCLC/TNBC/PDAC/MSS/OC/RCC/mCPRC

Novartis

Ⅰ

+ NZV930/PDR001

NCT03549000

Solid tumors

Novartis

Ⅰ

+ KAZ954

NCT04237649

TNBC

Novartis

Ⅰ

+ PDR001/LAG525

NCT03742349

NSCLC/RCC/pancreatic cancer/urothelial cancer/head and neck cancer/DLBCL/MSS/ TNBC/melanoma

Novartis

Ⅱ

+ PDR001

NCT03207867

RCC

Novartis

Ⅰ/Ⅰb

+ PDR001+ DFF332

NCT04895748

Etrumadenant(AB928)

Metastatic castration-resistant prostate cancer/prostate cancer

Surface Oncology

Ⅱ

+ SRF617 + zimberelimab

NCT05177770

NSCLC/HNSCC/breast cancer/CRC/melanoma/bladder cancer/OC/endometrial cancer/merkel cell carcinoma/gastroesophageal cancer/renal cell carcinoma/CRPC

Arcus

Ⅰ

+ Zimberelimab

NCT03629756

Head and neck cancer/squamous cell carcinoma of head and neck/oral cavity squamous cell carcinoma/oral cavity cancer/oropharynx cancer/oropharynx/squamous cell carcinoma/larynx cancer/pharynx cancer/hypopharynx cancer/hypopharynx squamous cell carcinoma

Arcus

+ Concurrent cisplatin/+ radiation therapy + zimberelimab

NCT04892875

Metastatic colorectal cancer

Arcus

Ⅰb/Ⅱ

+ Zimberelimab + mFOLFOX-6 + bevacizumab/+ zimberelimab + AB680

NCT04660812

Prostatic neoplasms, castration-resistant/androgen-resistant prostatic neoplasms/castration resistant prostatic neoplasms/prostatic cancer, castration-resistant

Arcus

Ⅰb/Ⅱ

+ Zimberelimab + enzalutamide/+ trumadenant + zimberelimab + docetaxel/+ zimberelimab/+ zimberelimab + AB680/+ AB680

NCT04381832

Gastro esophageal cancer/CRC

Arcus

Ⅰ/Ⅰb

+ mFOLFOX

NCT03720678

TBNC/OC

Arcus

Ⅰ/Ⅰb

+ PLD/+ NP/+ PLD + IPI-549

NCT03719326

NSCLC metastatic/NSCLC/nonsquamous non small cell neoplasm of lung/sensitizing EGFR gene mutation

Arcus

Ⅰ/Ⅰb

+ Carboplatin + pemetrexed/+ carboplatin + pemetrexed + pembrolizumab/+ zimberelimab + carboplatin + pemetrexed

NCT03846310

NSCLC/nonsquamous NSCLC/squamous NSCLC/lung cancer

Arcus

Ⅱ

+ Domvanalimab + zimberelimab

NCT04262856

NSCLC/non-small cell carcinoma

Arcus

Ⅱ

+ Zimberelimab + domvanalimab

NCT04791839

Rectal cancer

Arcus

Ⅱ

+ FOLFOX regimen + zimberelimab

NCT05024097

Prostate adenocarcinoma

Genentech

Ⅱ

+ Atezolizumab

NCT03821246

Pancreatic adenocarcinoma

Roche

Ⅰb/Ⅱ

+ Atezolizumab + chemotherapy

NCT03193190

CRC

Roche

Ⅰb/Ⅱ

Single agent/+ atezolizumab + regorafenib

NCT03555149

Inupadenant (EOS100850)

Solid tumor

iTeos

Ⅰ/Ⅰb

Single agent/+ pembrolizumab/+ chemotherapy

NCT03873883

Solid tumor

iTeos

Ⅰ

Single agent

NCT05117177

Advanced cancer/lung cancer/head and neck cancer/melanoma

iTeos

Ⅰ/Ⅱ

Inupadenant +EOS-448/inupadenant + pembrolizumab

NCT05060432

CS3005

Advanced solid tumors

CStone

Ⅰ

Single agent

NCT04233060

EXS21546

Oncology

Exscientia

Ⅰ

Single agent

NCT04727138

PBF-999

Advanced solid tumor

Palobiofarma

Ⅰ

Single agent

NCT03786484