Division of Gastrointestinal Surgery, University of Nottingham, E Floor West Block, Queens Medical Centre, Derby Road, Nottingham, NG7 2UH, UK.
J Transl Med. 2013 Jan 15;11:16. doi: 10.1186/1479-5876-11-16.
Host defences play a key role in tumour growth. Some of the benefits of chemotherapy may occur through modulation of these defences. The aim of this study was to define the status of regulatory cells in women with large and locally advanced breast cancers (LLABCs) undergoing neoadjuvant chemotherapy (NAC) and surgery.
Bloods were collected from patients (n=56) before, during and following NAC, and surgery. Controls (n=10) were healthy, age-matched females donors (HFDs). Blood mononuclear cells (BMCs) were isolated and T regulatory cells (Tregs) (n=31) determined. Absolute numbers (AbNs) of Tregs and myeloid-derived suppressor cells (MDSCs) were ascertained from whole blood (n=25). Reverse transcriptase polymerase chain reaction analysis determined Treg mRNA (n=16). In vitro production of Th1, Th2 and Th17 cytokines (n=30), was documented. Patients were classified as clinical responders by magnetic resonance mammography after two cycles of NAC and as pathological responders using established criteria, following surgery.
Patients with LLABCs had significantly increased circulating Tregs (≥ 6 fold AbN and percentage (%)) and MDSCs (≥ 1.5 fold AbN (p=0.025)). Percentage of FOXP3+ Tregs in blood predicted the response of the LLABCs to subsequent NAC (p=0.04). Post NAC blood Tregs (%) were significantly reduced in patients where tumours showed a good pathological response to NAC (p=0.05). Blood MDSCs (granulocytic, monocytic) were significantly reduced in all patients, irrespective of the pathological tumour response to chemotherapy. NAC followed by surgery failed to restore blood Tregs to normal levels. MDSCs, however, were reduced to or below normal levels by NAC alone. Invitro Th1 profile (IL-1β, IL-2, INF-γ, TNF-α) was significantly reduced (p ≤ 0.009), whilst Th2 (IL-4, IL-5) was significantly enhanced (P ≤ 0.004). Th1 and Th2 (IL-5) were unaffected by NAC and surgery. IL-17A was significantly increased (p ≤ 0.023) but unaffected by chemotherapy and surgery.
Women with LLABCs have abnormal blood regulatory cell levels (Tregs and MDSCs) and cytokine profiles (Th1, Th2, Th17). NAC followed by surgery failed to abolish the abnormal Treg and Th profiles. There was a significant correlation between the circulatory levels of Tregs and the pathological response of the breast cancers to NAC.
宿主防御在肿瘤生长中起着关键作用。化疗的一些益处可能通过调节这些防御机制而产生。本研究的目的是定义接受新辅助化疗（NAC）和手术的大局部晚期乳腺癌（LLABC）女性患者调节性细胞的状态。
在 NAC 前、期间和之后以及手术前从患者（n=56）和对照组（n=10）中采集血液。对照组为健康、年龄匹配的女性供体（HFD）。分离血液单核细胞（BMC）并确定 T 调节细胞（Tregs）（n=31）。通过全血确定 Treg 和髓源性抑制细胞（MDSCs）的绝对数量（AbN）（n=25）。逆转录聚合酶链反应分析确定 Treg mRNA（n=16）。记录了 Th1、Th2 和 Th17 细胞因子的体外产生（n=30）。根据 NAC 后两个周期的磁共振乳腺成像，将患者分类为临床反应者，并根据术后既定标准将其分类为病理反应者。
LLABC 患者的循环 Tregs（AbN 和百分比（%）≥ 6 倍）和 MDSCs（AbN≥1.5 倍（p=0.025））明显增加。血液中 FOXP3+Treg 的百分比预测了 LLABC 对随后 NAC 的反应（p=0.04）。在对 NAC 反应良好的肿瘤患者中，NAC 后血液 Tregs（%）明显降低（p=0.05）。无论化疗对肿瘤的病理反应如何，所有患者的血液 MDSCs（粒细胞、单核细胞）均明显减少。NAC 单独即可将 MDSCs 降低至正常水平以下。然而，MDSCs 被 NAC 单独降低至或低于正常水平。体外 Th1 谱（IL-1β、IL-2、INF-γ、TNF-α）明显降低（p ≤ 0.009），而 Th2（IL-4、IL-5）明显增强（P ≤ 0.004）。NAC 和手术均未改变 Th1 和 Th2（IL-5）。IL-17A 明显增加（p ≤ 0.023），但不受化疗和手术影响。
患有 LLABC 的女性患者存在异常的血液调节性细胞水平（Tregs 和 MDSCs）和细胞因子谱（Th1、Th2、Th17）。NAC 后手术未能消除异常的 Treg 和 Th 谱。Tregs 循环水平与乳腺癌对 NAC 的病理反应之间存在显著相关性。
