Intratumoral TIGIT+CD8+T-cell infiltration determines poor prognosis and immune evasion in patients with muscle-invasive bladder cancer
Intratumoral TIGIT+CD8+T-cell infiltration determines poor prognosis and immune evasion in patients with muscle-invasive bladder cancer
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瘤内 TIGIT CD8 T 细胞浸润决定肌层浸润性膀胱癌患者的不良预后和免疫逃避
DOI：
10.1136/jitc-2020-000978
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发表时间：
2020-01-01
影响因子：
10.9
通讯作者：
Zhang, Weijuan
中科院分区：
文献类型：
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作者：
Liu, Zhaopei;Zhou, Quan;Zhang, Weijuan
背景 T 细胞免疫球蛋白和 ITIM 结构域 (TIGIT) 被认为是一种新型检查点受体，可以通过介导肿瘤中 T 细胞耗竭来促进免疫逃逸。然而，肿瘤内TIGIT(+)CD8(+)T细胞在肌层浸润性膀胱癌(MIBC)中的临床意义和免疫环境相关性仍有待进一步探讨。方法对来自两个临床中心（中山医院，n=141；上海肿瘤中心，n=118）的259例MIBC患者进行分析，通过免疫组织化学评估TIGIT(+)CD8(+)T细胞的预后价值和免疫背景关联。通过流式细胞术检查 26 名 MIBC 患者的新鲜肿瘤组织样本，以发现该 CD8 亚群的表型。结果瘤内TIGIT(+)CD8(+)T细胞的高浸润预示着MIBC的总生存期(OS)和无复发生存期(RFS)较差。对于TIGIT(+)CD8(+)细胞浸润较低的II期MIBC患者，辅助化疗(ACT)可显着延长其OS和RFS。瘤内TIGIT(+)CD8(+)T细胞丰度与CD8(+)T细胞毒性受损相关，并产生免疫抑制细胞因子IL-10。对肿瘤浸润免疫细胞景观的进一步分析表明，TIGIT(+)CD8(+)T细胞与抑制性免疫环境相关，包括Th2细胞、调节性T细胞、肥大细胞和中性粒细胞。结论 瘤内 TIGIT(+)CD8(+)T 细胞丰度可作为临床结果的独立预测因子和 ACT 反应性较差的预测生物标志物。肿瘤内TIGIT(+)CD8(+)T细胞丰度与CD8(+)T细胞抗肿瘤免疫减弱和免疫抑制背景丰度相关，突出了TIGIT(+)CD8(+)T细胞的促肿瘤作用。
Background T-cell immunoglobulin and ITIM domain (TIGIT) is identified as a novel checkpoint receptor that can facilitate immune escape via mediating T-cell exhaustion in tumors. However, the clinical significance and immune contexture correlation of intratumoral TIGIT(+)CD8(+)T-cells remain to be further explored in muscle-invasive bladder cancer (MIBC). Methods 259 patients with MIBC from two clinical centers (Zhongshan Hospital, n=141; Shanghai Cancer Center, n=118) were analyzed to evaluate the prognostic value and immune contexture association of TIGIT(+)CD8(+)T-cells through immunohistochemistry. Fresh tumor tissue samples from 26 patients with MIBC were examined to discover the phenotype of this CD8 subpopulation by flow cytometry. Results High infiltration of intratumoral TIGIT(+)CD8(+)T-cells predicted poor overall survival (OS) and recurrence-free survival (RFS) in MIBC. For patients with stage II MIBC with low infiltration of TIGIT(+)CD8(+)cells, adjuvant chemotherapy (ACT) could significantly prolong their OS and RFS. Intratumoral TIGIT(+)CD8(+)T-cell abundance was correlated with impaired CD8(+)T-cell cytotoxicity and exhibited production of immunosuppressive cytokine IL-10. Further analysis of tumor-infiltrating immune cell landscape revealed TIGIT(+)CD8(+)T-cells were associated with suppressive immune contexture, including Th2 cells, regulatory T-cells, mast cells and neutrophils. Conclusion Intratumoral TIGIT(+)CD8(+)T-cell abundance could serve as an independent prognosticator for clinical outcome and a predictive biomarker for inferior ACT responsiveness. Intratumoral TIGIT(+)CD8(+)T-cell abundance correlated with dampened CD8(+)T-cell antitumor immunity and immunosuppressive contexture abundance, highlighting a tumor-promoting role of TIGIT(+)CD8(+)T-cells.