CCR8 blockade primes anti-tumor immunity through intratumoral regulatory T cells destabilization in muscle-invasive bladder cancer
CCR8 blockade primes anti-tumor immunity through intratumoral regulatory T cells destabilization in muscle-invasive bladder cancer
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CCR8 阻断通过肌层浸润性膀胱癌的瘤内调节性 T 细胞不稳定来启动抗肿瘤免疫
DOI：
10.1007/s00262-020-02583-y
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发表时间：
2020-05-04
影响因子：
5.8
通讯作者：
Xu, Jiejie
中科院分区：
文献类型：
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作者：
Wang, Tao;Zhou, Quan;Xu, Jiejie
调节性T细胞（TCRs）在免疫抑制性肿瘤微环境的发展中起着重要作用。全身性Treg耗竭是不受欢迎的，因为Treg在维持免疫稳态和预防自身免疫中起关键作用。最近，CCR 8已被鉴定为在肿瘤内T细胞上表达的重要趋化因子受体，并且已知对于CCR 8 + Treg介导的免疫抑制至关重要。然而，肿瘤内CCR 8 + TcR的内在分子机制和临床意义仍然知之甚少。在这项研究中，对来自两个独立临床中心的259例肌层浸润性膀胱癌（MIBC）患者进行了回顾性分析，以通过免疫组化探讨CCR 8 + TCR 4的预后价值。83个新鲜的MIBC样本和来自癌症基因组图谱的数据被用于通过流式细胞术、离体干预实验和生物信息学分析来评估免疫细胞的比例和功能。结果表明，TCR 8基因在肿瘤内的表达稳定，并通过上调转录因子FOXO 1和c-MAF的表达而增强其抑制功能。高水平的CCR 8 + TcR与免疫耐受相关，并预测较差的生存率和对化疗的低治疗反应性。此外，发现CCR 8阻断可使肿瘤内TCR 4不稳定为脆性表型，伴随抗肿瘤免疫的再激活和MIBC中抗PD-1治疗益处的增加。综上所述，这些结果表明，CCR 8 + T细胞是一种稳定的Treg亚型，是MIBC免疫治疗中有希望的治疗靶点。
Regulatory T cells (Tregs) play a major role in the development of an immunosuppressive tumor microenvironment. Systemic Treg depletion is not favored because of the critical role of Tregs in maintaining immune homeostasis and preventing the autoimmunity. Recently, CCR8 has been identified as an important chemokine receptor expressed on intratumoral Tregs and is known to be critical for CCR8+Treg-mediated immunosuppression. However, the inherent molecular mechanisms and clinical significance of intratumoral CCR8+Tregs remain poorly understood. In this study, a retrospective analysis of 259 muscle-invasive bladder cancer (MIBC) patients from two independent clinic centers was conducted to explore the prognostic merit of CCR8+Tregs via immunohistochemistry. Eighty-three fresh MIBC samples and data from the Cancer Genome Atlas were used to evaluate the proportion and function of immune cells via flow cytometry, ex vivo intervention experiments and bioinformatics analysis. It was found that the CCR8 expression by intratumoral Tregs maintained the stability and potentiated their suppressive function by upregulating the expression of transcript factors FOXO1 and c-MAF. High level of CCR8+Tregs was associated with the immune tolerance and predicted poor survival and inferior therapeutic responsiveness to chemotherapy. Moreover, it was revealed that CCR8 blockade could destabilize intratumoral Tregs into a fragile phenotype accompanied with reactivation of antitumor immunity and augment of anti-PD-1 therapeutic benefits in MIBC. In summary, those results suggested that CCR8+Tregs represented a stable Treg subtype and a promising therapeutic target in the immunotherapy of MIBC.