中南大学湘雅医院皮肤科陈翔和刘洪团队合作取得一项新成果。他们提出ADORA1的抑制通过调节ATF3-PD-L1轴促进肿瘤免疫逃逸。2020年3月16日出版的《癌细胞》发表了这项成果。

研究人员表示肿瘤ADORA1缺失抑制了人黑色素瘤细胞系的细胞体外生长，并抑制了体内免疫缺陷异种移植物中肿瘤进展。但是，这种缺失会诱导PD-L1水平的上调，从而使体外共培养的T细胞失活，在体内削弱抗肿瘤免疫力，并降低具有免疫功能的小鼠模型的抗肿瘤功效。

从功能上，PD-1 mAb治疗可增强ADORA1缺失或ADORA1拮抗剂治疗的黑色素瘤和NSCLC免疫小鼠模型的功效。从机制上，他们将ATF3鉴定为转录上调PD-L1表达的因子。肿瘤ATF3缺失提高了ADORA1拮抗剂治疗黑素瘤和NSCLC异种移植物的效果。

研究人员观察到，PD-1 mAb治疗的NSCLC患者无应答者的肿瘤组织中有更高的ADORA1，更低的ATF3和更低的PD-L1表达水平。

附：英文原文

Title: ADORA1 Inhibition Promotes Tumor Immune Evasion by Regulating the ATF3-PD-L1 Axis

Author: Hong Liu, Xinwei Kuang, Yongchang Zhang, Youqiong Ye, Jialu Li, Long Liang, Zuozhong Xie, Liang Weng, Jia Guo, Hui Li, Fangyu Ma, Xiaodan Chen, Shuang Zhao, Juan Su, Nong Yang, Fang Fang, Yang Xie, Juan Tao, Jianglin Zhang, Mingliang Chen, Cong Peng, Lunquan Sun, Xin Zhang, Jing Liu, Leng Han, Xiaowei Xu, Mien-Chie Hung, Xiang Chen

Issue&Volume: 2020/03/16

Abstract: Here, we show that tumor ADORA1 deletion suppresses cell growth in human melanomacell lines in vitro and tumor development in vivo in immune-deficient xenografts. However, this deletion induces the upregulation ofPD-L1 levels, which inactivates cocultured T cells in vitro, compromises anti-tumor immunity in vivo, and reduces anti-tumor efficacy in an immune-competent mouse model. Functionally,PD-1 mAb treatment enhances the efficacy of ADORA1-deficient or ADORA1 antagonist-treated melanoma and NSCLC immune-competent mousemodels. Mechanistically, we identify ATF3 as the factor transcriptionally upregulatingPD-L1 expression. Tumor ATF3 deletion improves the effect of ADORA1 antagonist treatmentof melanoma and NSCLC xenografts. We observe higher ADORA1, lower ATF3, and lowerPD-L1 expression levels in tumor tissues from nonresponders among PD-1 mAb-treatedNSCLC patients.

DOI: 10.1016/j.ccell.2020.02.006

Source: https://www.cell.com/cancer-cell/fulltext/S1535-6108(20)30095-7