Tumor-infiltrating CD39+CD8+ T cells determine poor prognosis and immune evasion in clear cell renal cell carcinoma patients
Tumor-infiltrating CD39+CD8+ T cells determine poor prognosis and immune evasion in clear cell renal cell carcinoma patients
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肿瘤浸润 CD39( )CD8( ) T 细胞决定透明细胞肾细胞癌患者的不良预后和免疫逃避
DOI：
10.1007/s00262-020-02563-2
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发表时间：
2020-04-18
影响因子：
5.8
通讯作者：
Xu, Jiejie
中科院分区：
文献类型：
--
作者：
Qi, Yu;Xia, Yu;Xu, Jiejie
目的肿瘤微环境在肾透明细胞癌（ccRCC）的发生发展中起重要作用，其预后价值尚不清楚。近年来的研究表明，肿瘤浸润性CD 39（+）CD 8（+）T细胞数量丰富，但其功能尚不清楚。我们的目的是评估CD 39（+）CD 8（+）T细胞在ccRCC中的临床价值，并寻求潜在的治疗靶点。实验设计我们在中山医院回顾性队列的243例ccRCC患者中，以免疫化学方法评估了CD 39（+）CD 8（+）T细胞的临床价值。收集中山医院新鲜肿瘤标本（n = 48）、非肿瘤组织和外周血进行流式细胞术分析，以分析免疫细胞功能。评估了酪氨酸激酶抑制剂（TKI）在该亚群中的生存获益。生存分析采用Kaplan-Meier分析和考克斯回归模型。在TCGA KIRC队列和scRNA-seq队列中进行生物信息学分析。结果我们发现，CD 39（+）CD 8（+）T细胞的积累表明预后不良（p < 0.0001），并表明TKI治疗的治疗效益（p = 0.015）。CD 39（+）CD 8（+）T细胞显示TNF-α和IFN-γ降低，PD-1和TIM-3表达升高。对ccRCC中肿瘤浸润免疫细胞景观的进一步分析揭示了CD 39（+）CD 8（+）T细胞与TcB（p = 0.037）和M2极化巨噬细胞（p < 0.0001）之间的正相关性。最后，抑制CD 39部分恢复了CD 8（+）T细胞的抗肿瘤功能。结论高CD 39（+）CD 8（+）T细胞提示ccRCC患者预后不良，可能与CD 39（+）CD 8（+）T细胞抗肿瘤功能受损有关，提示TKI治疗有益。[图形]。
Purpose Tumor microenvironment is important in the progression of clear cell renal cell carcinoma (ccRCC), and its prognostic value is still unclear. Recent reports demonstrated tumor-infiltrating CD39(+)CD8(+) T cells are abundant, but their function remains obscure. We aim to assess clinical value of CD39(+)CD8(+) T cells and seek a potential therapeutic target in ccRCC. Experimental design We immunohistochemically evaluated clinical value of CD39(+)CD8(+) T cells in a retrospective Zhongshan Hospital cohort of 243 ccRCC patients. Fresh tumor samples (n = 48), non-tumor tissues and peripheral blood for flow cytometry analyses were collected to analyze immune cell functions from Zhongshan Hospital. The survival benefit of tyrosine kinase inhibitors (TKIs) in this subpopulation was evaluated. Kaplan-Meier analysis and COX regression model were applied for survival analyses. Bioinformatics analysis performed in TCGA KIRC cohort and the scRNA-seq cohort. Results We found that accumulation of CD39(+)CD8(+) T cells indicated poor prognosis (p < 0.0001) and indicated therapeutic benefit of TKIs therapy (p = 0.015). CD39(+)CD8(+) T cells showed decreased TNF-alpha and IFN-gamma with elevated PD-1 and TIM-3 expression. Further analysis of tumor-infiltrating immune cell landscape in the ccRCC revealed the positive correlation between CD39(+)CD8(+) T cells and Tregs (p = 0.037) and M2-polarized macrophages (p < 0.0001). Finally, inhibition of CD39 partially restores the anti-tumor function of CD8(+) T cells. Conclusions High CD39(+)CD8(+) T cells indicated poor prognosis in ccRCC, due to impaired anti-tumor function of CD39(+)CD8(+) T cells and indicated therapeutic benefit of TKIs therapy.[GRAPHICS].