Department of Gynecological Oncology, Shanghai Cancer Center, Fudan University, Shanghai, China.
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
Int J Cancer. 2020 Apr 1;146(7):1993-2006. doi: 10.1002/ijc.32782. Epub 2019 Nov 29.
Regulatory T cells (Tregs) are crucial for the maintenance of peripheral tolerance, but they also limit beneficial responses through cancer-induced immunoediting. The roles of Treg subsets in cervical squamous cell carcinoma (CSCC) are currently unknown. Here, we aimed to perform an extensive study with an increased resolution of the Treg compartment in the peripheral blood and tumor tissues of CSCC patients. We first identified that an HLADR Treg population in the peripheral blood was significantly increased in CSCC patients compared to precancer patients and healthy donors. We found that HLADR Tregs express high levels of a panel of inhibition and activation markers and the TCR-responsive transcription factors BATF and IRF4. However, this Treg subset showed reduced calcium influx after TCR crosslinking. In addition, HLADR Tregs are highly proliferative and vulnerable to apoptosis. Further studies demonstrated that the HLADR Tregs display high levels of suppressive activity. Quantitative multiplexed immunohistochemistry revealed that an increase in the number of tumor-infiltrating HLADR Tregs is associated with unfavorable classical risk parameters of advanced disease stage and stromal invasion. Context-based quantification revealed that a high frequency of stromal HLADR Tregs in patients is significantly associated with worse progression-free survival. In the current study, we characterized a population of highly activated and immunosuppressive HLADR Tregs in CSCC patients. An increased HLADR Treg frequency may be a potential biomarker to stratify CSCC patients and evaluate therapeutic efficacies in personalized immuno-oncology studies.
调节性 T 细胞（Tregs）对于维持外周耐受至关重要，但它们也通过癌症诱导的免疫编辑限制了有益的反应。Treg 亚群在宫颈鳞状细胞癌（CSCC）中的作用目前尚不清楚。在这里，我们旨在通过增加 CSCC 患者外周血和肿瘤组织中 Treg 区室的分辨率来进行广泛的研究。我们首先确定，与癌前患者和健康供体相比，CSCC 患者外周血中的 HLADR Treg 群体显著增加。我们发现 HLADR Tregs 表达高水平的一组抑制和激活标志物以及 TCR 反应性转录因子 BATF 和 IRF4。然而，这种 Treg 亚群在 TCR 交联后显示出钙内流减少。此外，HLADR Tregs 具有高增殖性和易凋亡性。进一步的研究表明，HLADR Tregs 具有高水平的抑制活性。定量多重免疫组化显示，肿瘤浸润性 HLADR Tregs 数量的增加与晚期疾病阶段和基质浸润的不利经典风险参数相关。基于背景的定量显示，患者中基质 HLADR Tregs 的高频率与无进展生存期明显相关。在本研究中，我们描述了 CSCC 患者中一群高度活化和免疫抑制的 HLADR Tregs。增加的 HLADR Treg 频率可能是分层 CSCC 患者和评估个性化免疫肿瘤学研究中治疗效果的潜在生物标志物。
