CCR5 blockade inflames antitumor immunity in BAP1-mutant clear cell renal cell carcinoma
CCR5 blockade inflames antitumor immunity in BAP1-mutant clear cell renal cell carcinoma
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CCR5 阻断会加剧 BAP1 突变型透明细胞肾细胞癌的抗肿瘤免疫
DOI：
10.1136/jitc-2019-000228
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发表时间：
2020
影响因子：
10.9
通讯作者：
Jiejie Xu
中科院分区：
文献类型：
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作者：
Quan Zhou;Yangyang Qi;Zewei Wang;Han Zeng;Hongyu Zhang;Zhaopei Liu;Qiuren Huang;Ying Xiong;Jiajun Wang;Yuan Chang;Qi Bai;Yu Xia;Yiwei Wang;Li Liu;Le Xu;Bo Dai;Jianming Guo;Yu Zhu;Weijuan Zhang;Jiejie Xu
背景BRCA 1相关蛋白1（BAP 1）突变型肾透明细胞癌（ccRCC）患者预后较差。C-C趋化因子受体5（C-C chemokine receptor 5，CCR 5）在肾细胞癌的发生发展中起重要作用，其在BAP 1突变型肿瘤中的表达升高。用人ccRCC肿瘤和鼠肿瘤模型进行体外和体内研究。通过免疫组化、流式细胞术、实时荧光PCR和ELISA检测BAP 1与CCR 5或其配体之间的结合。采用Kaplan-Meier曲线比较不同亚群患者的生存率。使用人ccRCC肿瘤和小鼠models.ResultsCCR5阻断的治疗效果进行了验证BAP 1突变患者ccRCC中CCR 5及其配体的表达升高。在BAP 1-低组患者中，CCR 5高表达表明预后不良。CCR 5阻断延长了荷瘤小鼠的存活时间，导致T细胞的细胞毒性和树突状细胞的抗原呈递增强，但抑制了免疫检查点的表达。CCR 5配体可以将CCR 5+调节性T细胞募集到肿瘤微环境中。此外，BAP 1突变型ccRCC肿瘤细胞分泌CCR 5配体，其增加程序性细胞死亡配体1的表达。然而，这两个过程都可以被CCR 5阻断所抑制。结论BAP 1突变型ccRCC中CCR 5的表达导致免疫抑制微环境的改变。靶向CCR 5可以为患者提供潜在的治疗获益。试验注册号NCT 01358721，CA 209 -009。
BackgroundPatients with BRCA1-associated protein 1 (BAP1)-mutant clear cell renal cell carcinoma (ccRCC) have worse prognosis. C-C chemokine receptor 5 (CCR5) plays an important role in ccRCC development and its expression is elevated in BAP1-mutant tumors.Methods533 patients with ccRCC from The Cancer Genome Atlas cohort and 797 patients with ccRCC from the Shanghai cohort were enrolled. In vitro and in vivo studies were conducted with human ccRCC tumors and murine tumor models. The association between BAP1 and CCR5 or its ligands was assessed by immunohistochemistry, flow cytometry, real-time PCR and ELISA. Survival was compared between different subpopulations of patients using Kaplan-Meier curve. Therapeutic effect of CCR5 blockade was validated using human ccRCC tumors and murine models.ResultsExpression of CCR5 and its ligands were elevated in BAP1-mutant patients with ccRCC. High CCR5 expression was indicative of poor prognosis in BAP1-low group of patients. CCR5 blockade prolonged the survival of tumor-bearing mice, resulting in enhanced cytotoxicity of T cells and antigen presentation of dendritic cells but repressed immune checkpoint expression. CCR5 ligands could recruit CCR5+regulatory T cells to the tumor microenvironment. Additionally, BAP1-mutant ccRCC tumor cells secreted CCR5 ligands, which increased programmed cell death ligand 1 expression. However, both processes could be inhibited by CCR5 blockade. Study limitations include the unclear impact of CCR5 expressed by other cell populations.ConclusionsCCR5 in BAP1-mutant ccRCC results in an immune-suppressive microenvironment. Targeting CCR5 could provide a potential therapeutic benefit for patients.Trial registration numberNCT01358721, CA209-009.