Authors' Affiliations: University of Pittsburgh Cancer Institute; University of Pittsburgh School of Medicine; Departments of Pathology, Immunology, and Otolaryngology, Pittsburgh, Pennsylvania; Department of Otolaryngology, University of Essen, Germany; and Department of Surgery, Fukushima Medical University, Fukushima, Japan.
Clin Cancer Res. 2013 Dec 1;19(23):6585-96. doi: 10.1158/1078-0432.CCR-13-0900. Epub 2013 Oct 4.
Regulatory T cells (Treg) accumulate in tumor tissues and the peripheral blood of cancer patients and may persist after therapies. This cross-sectional study examines effects of adjuvant chemoradiotherapy (CRT) on Treg numbers and function in head and neck squamous cell carcinoma (HNSCC) patients.
The frequency and absolute numbers of CD4(+), ATP-hydrolyzing CD4(+)CD39(+) and CD8(+) T cells, and expression levels of CD39, CD25, TGF-β-associated LAP and GARP on Treg were measured by flow cytometry in 40 healthy donors (NC) and 71 HNSCC patients [29 untreated with active disease (AD); 22 treated with surgery; 20 treated with CRT]. All treated subjects had no evident disease (NED) at the time of phlebotomy. In an additional cohort of 40 subjects with AD (n = 15), NED (n = 10), and NC (n = 15), in vitro sensitivity of CD4(+) T-cell subsets to cisplatin and activation-induced cell death (AICD) was tested in Annexin V-binding assays.
CRT decreased the frequency of circulating CD4(+) T cells (P < 0.002) but increased that of CD4(+)CD39(+) Treg (P ≤ 0.001) compared with untreated or surgery-only patients. Treg frequency remained elevated for >3 years. CRT increased surface expression of LAP, GARP, and CD39 on Treg. In vitro Treg were resistant to AICD or cisplatin but conventional CD4(+) T cells (Tconv) were not. CRT-induced Treg from AD or NC subjects upregulated prosurvival proteins whereas Tconv upregulated proapoptotic Bax.
Highly suppressive, cisplatin-resistant Treg increase in frequency and persist after CRT and could be responsible for suppression of antitumor immune responses and recurrence in HNSCC.
调节性 T 细胞（Treg）在肿瘤组织和癌症患者的外周血中积聚，并且在治疗后可能持续存在。本横断面研究探讨了辅助放化疗（CRT）对头颈部鳞状细胞癌（HNSCC）患者 Treg 数量和功能的影响。
通过流式细胞术测量了 40 名健康供体（NC）和 71 名 HNSCC 患者[29 名未接受治疗的活动性疾病（AD）；22 名接受手术治疗；20 名接受 CRT 治疗]中 CD4+、ATP 水解 CD4+CD39+和 CD8+T 细胞的频率和绝对数量，以及 Treg 上 CD39、CD25、TGF-β相关 LAP 和 GARP 的表达水平。所有接受治疗的患者在采血时均无明显疾病（NED）。在另一项包含 40 名 AD 患者（n=15）、NED 患者（n=10）和 NC 患者（n=15）的队列中，通过 Annexin V 结合测定法测试了 CD4+T 细胞亚群对顺铂和激活诱导的细胞死亡（AICD）的体外敏感性。
与未治疗或仅接受手术的患者相比，CRT 降低了循环 CD4+T 细胞的频率（P<0.002），但增加了 CD4+CD39+Treg 的频率（P≤0.001）。Treg 频率持续升高超过 3 年。CRT 增加了 Treg 表面表达的 LAP、GARP 和 CD39。体外 Treg 对 AICD 或顺铂具有抗性，但常规 CD4+T 细胞（Tconv）没有。来自 AD 或 NC 患者的 CRT 诱导的 Treg 上调了促生存蛋白，而 Tconv 上调了促凋亡 Bax。
高度抑制性、顺铂耐药的 Treg 频率增加，并在 CRT 后持续存在，可能是导致 HNSCC 中抗肿瘤免疫反应抑制和复发的原因。
