Intratumoral CXCL13(+)CD8(+)T cell infiltration determines poor clinical outcomes and immunoevasive contexture in patients with clear cell renal cell carcinoma.
Intratumoral CXCL13(+)CD8(+)T cell infiltration determines poor clinical outcomes and immunoevasive contexture in patients with clear cell renal cell carcinoma.
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瘤内 CXCL13( )CD8( )T 细胞浸润决定了透明细胞肾细胞癌患者不良的临床结果和免疫逃避环境。
DOI：
10.1136/jitc-2020-001823
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发表时间：
2021-03
影响因子：
10.9
通讯作者：
Xu J
中科院分区：
文献类型：
--
作者：
Dai S;Zeng H;Liu Z;Jin K;Jiang W;Wang Z;Lin Z;Xiong Y;Wang J;Chang Y;Bai Q;Xia Y;Liu L;Zhu Y;Xu L;Qu Y;Guo J;Xu J
趋化因子（C-X-C motif）配体13（CXCL 13）是一种选择性趋化B细胞、滤泡辅助性CD 4 +T细胞（TFH）的产物和三级淋巴样结构（TLS）的贡献者。虽然TFH产生的CXCL 13的分泌和功能已被深入研究，但CD 8 +T细胞分泌的CXCL 13的免疫功能和预后意义仍然没有被揭示。本研究旨在探讨CXCL 13 + CD 8 +T细胞在肾透明细胞癌（ccRCC）中的临床价值。我们分析了来自中山医院队列（n=223）和癌症基因组图谱队列（n=532）的共755例患者的预后价值和与CXCL 13 + CD 8 +T细胞浸润水平相关的免疫状况。对42例肿瘤组织标本进行CXCL 13 + CD 8 +T细胞和总CD 8 +T细胞的体外分析。应用免疫组织化学（IHC）和流式细胞术来表征免疫细胞并描绘ccRCC中的肿瘤微环境（TME）。肿瘤内CXCL 13 + CD 8 +T细胞丰度与较差的总生存期和无病生存期相关。CXCL 13 + CD 8 +T细胞具有较高水平的程序性细胞死亡蛋白1（PD-1）、T细胞免疫球蛋白粘蛋白3（Tim-3）、具有IG和ITIM结构域的T细胞免疫受体（TIGIT）和细胞毒性T淋巴细胞相关蛋白4（CTLA-4）等免疫检查点，较高的Ki-67表达和较低的肿瘤坏死因子α（TNF-α）、干扰素γ（IFN-γ）表达。高水平CXCL 13 + CD 8 +T细胞浸润亚群的总CD 8 +T细胞表现为耗竭性标志物（PD-1、Tim-3、TIGIT）升高，活化性标志物（TNF-α、IFN-γ）下降，但无数量变化。此外，肿瘤内CXCL 13 + CD 8 +T细胞的丰度与免疫逃避性TME相关，伴随着T辅助细胞2、肿瘤相关巨噬细胞、Foxp 3+调节性T细胞、TLS的增加和自然杀伤细胞、GZMB+细胞的减少。肿瘤内CXCL 13 + CD 8 +T细胞浸润表明ccRCC患者的临床结局较差。CXCL 13 + CD 8 +T细胞耗竭标志物增多，效应分子减少，增殖能力增强。CXCL 13 + CD 8 +T细胞的丰度损害总CD 8 +T细胞的免疫功能。肿瘤内CXCL 13 + CD 8 +T细胞丰度与免疫逃避结构相关。CXCL 13 + CD 8 +T细胞的丰度是ccRCC治疗的独立指标和潜在的免疫靶向标志物。
Chemokine (C-X-C motif) ligand 13 (CXCL13) was known as a selective chemotaxis for B cells, a product of follicular helper CD4+T cells (TFH) and a contributor to tertiary lymphoid structures (TLS). Although secretion and function of CXCL13 produced by TFH have been deeply explored, the immune function and prognostic significance of CXCL13 secreted by CD8+T cells still remain unrevealed. This study aims to investigate the clinical merit of CXCL13+CD8+T cells in clear cell renal cell carcinoma (ccRCC). We analyzed prognostic value and immune contexture that associated with CXCL13+CD8+T cells infiltration level in a total of 755 patients from Zhongshan Hospital cohort (n=223) and The Cancer Genome Atlas cohort (n=532). In vitro analyses were conducted on 42 samples of resected tumor tissue from Zhongshan Hospital in order to detect the immune status of CXCL13+CD8+T cells and total CD8+T cells. Immunohistochemistry (IHC) and flow cytometry were applied to characterize immune cells and portray the tumor microenvironment (TME) in ccRCC. Intratumoral CXCL13+CD8+T cells abundance was associated with inferior overall survival and disease-free survival. CXCL13+CD8+T cells possessed higher level of immune checkpoints like programmed cell-death protein 1 (PD-1), T-cell immunoglobulin mucin 3 (Tim-3), T cell immunoreceptor with Ig and ITIM domains (TIGIT) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), higher Ki-67 expression and lower tumor necrosis factor α (TNF-α), interferon γ (IFN-γ) expression. Total CD8+T cells in high-level CXCL13+CD8+T cells infiltration subgroup exhibited elevated exhausted markers (PD-1, Tim-3, TIGIT) and descended activated markers (TNF-α, IFN-γ) without quantity variance. Furthermore, the abundance of intratumoral CXCL13+CD8+T cell was correlated with immunoevasive TME accompanied by increased T helper 2 cells, tumor-associated macrophages, Foxp3+ regulatory T cells, TLS and decreased natural killer cells, GZMB+ cells. Intratumoral CXCL13+CD8+T cells infiltration indicated inferior clinical outcome in patients with ccRCC. CXCL13+CD8+T cells possessed increased exhausted markers, decreased effector molecules and better proliferation ability. CXCL13+CD8+T cells abundance impaired total CD8+T cells’ immune function. Intratumoral CXCL13+CD8+T cells abundance was associated with immunoevasive contexture. The abundance of CXCL13+CD8+T cells was an independent prognosticator and a potential immunotherapeutic target marker for ccRCC treatment.