Tumor-infiltrating TNFRSF9(+) CD8(+) T cells define different subsets of clear cell renal cell carcinoma with prognosis and immunotherapeutic response.
Tumor-infiltrating TNFRSF9(+) CD8(+) T cells define different subsets of clear cell renal cell carcinoma with prognosis and immunotherapeutic response.
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肿瘤浸润性 TNFRSF9( ) CD8( ) T 细胞定义了透明细胞肾细胞癌的不同亚群及其预后和免疫治疗反应
DOI：
10.1080/2162402x.2020.1838141
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发表时间：
2020-10-27
期刊：
影响因子：
7.2
通讯作者：
Xu J
中科院分区：
文献类型：
--
作者：
Li Y;Wang Z;Jiang W;Zeng H;Liu Z;Lin Z;Qu Y;Xiong Y;Wang J;Chang Y;Bai Q;Wang Y;Liu L;Zhu Y;Xu L;Xia Y;Guo J;Xu J
摘要 目的 肿瘤坏死受体超家族（TNFRSF）在调节 CD8+ T 细胞功能中发挥重要作用。在本研究中，我们探讨了 TNFRSF9+ CD8+ T 细胞在透明细胞肾细胞癌 (ccRCC) 中的临床意义和免疫特征。方法通过免疫组织化学方法测定我院 ZS 队列中免疫细胞的浸润情况，并通过 Cox 回归进一步确定其预后价值。通过流式细胞术测定 29 个新鲜肿瘤样本中 ccRCC 中 CD8+ T 细胞的功能状态。对 TCGA 队列和其他数据集进行了计算机分析，以进一步证明我们的发现。结果 在 ZS 队列 (p = .0016) 和 TCGA-KIRC 队列 (p = .018) 中，高 TNFRSF9+ CD8+ T 细胞浸润与较差的总体生存率相关。与 TNFRSF9 阴性细胞相比，TNFRSF9+ CD8+ T 细胞表达更高的耗竭标记物（PD-1、TIM-3、CTLA-4 和 TIGIT）和效应标记物（IFN-γ、GZMB、CD107a 和 Ki-67）。计算机分析表明，CD8+ T 细胞中 TNFRSF9 的表达与 IFNG、GZMK、MKI-67、PDCD1、HAVCR2、TIGIT 和 CTLA-4 显着相关。然而，在接受纳武单抗而非依维莫司治疗的患者中，较高的 TNFRSF9 特征与较大的肿瘤尺寸缩小 (p = .003) 和更好的无进展生存期 (p = .012) 相关。结论 TNFRSF9+ CD8+ T 细胞同时具有耗竭和效应表型，被认为是 ccRCC 的不良预后因素。这些细胞富集与更好的免疫治疗反应相关，这表明这些细胞在免疫治疗中可能至关重要。
ABSTRACT Objectives Tumor necrosis receptor super family (TNFRSF) plays an important role in regulating the function of CD8+ T cells. In this study, we explored the clinical significance and immune profile of TNFRSF9+ CD8+ T cells in clear cell renal cell carcinoma (ccRCC) Methods The infiltration of immune cells was determined by immunohistochemistry in ZS cohort from our hospital and their prognostic value was further determined by Cox regression. Functional status of CD8+ T cells in ccRCC was determined by flow cytometry in 29 fresh tumor samples. In silico analysis on a TCGA cohort and other datasets was performed to further demonstrate our findings. Results High TNFRSF9+ CD8+ T cells infiltration was associated with inferior overall survival in ZS cohort (p = .0016) and TCGA-KIRC cohort (p = .018). TNFRSF9+ CD8+ T cells expressed higher exhaustion markers (PD-1, TIM-3, CTLA-4, and TIGIT), and effector markers (IFN-γ, GZMB, CD107a, and Ki-67), than their TNFRSF9 negative counterparts. In silico analysis indicated the expression of TNFRSF9 was significantly correlated with IFNG, GZMK, MKI-67, PDCD1, HAVCR2, TIGIT, and CTLA-4 in CD8+ T cells. However, higher TNFRSF9 signature was correlated with larger tumor size shrinkage (p = .003) and better progression-free survival (p = .012) in patients treated with nivolumab but not everolimus. Conclusion TNFRSF9+ CD8+ T cells, which possessed both exhaustion and effector phenotype, were identified as an adverse prognosticator in ccRCC. These cells enrichment was associated with better immunotherapy response which indicated these cells potentially be crucial in immunotherapy.