부산대학교 도서관

Background 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. Methods 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. Results Patients with LLABCs had significantly increased circulating Tregs ([greater than or equai to] 6 fold AbN and percentage (%)) and MDSCs ([greater than or equai to] 1.5 fold AbN (p = 0.025)). Percentage of FOXP3.sup.+ 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-1[beta], IL-2, INF-[gamma], TNF-[alpha]) was significantly reduced (p [less than or equai to] 0.009), whilst Th2 (IL-4, IL-5) was significantly enhanced (P [less than or equai to] 0.004). Th1 and Th2 (IL-5) were unaffected by NAC and surgery. IL-17A was significantly increased (p [less than or equai to] 0.023) but unaffected by chemotherapy and surgery. Conclusion 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. Keywords: Breast cancer, Tregs, Myeloid-derived suppressor cells, Cytokines, Chemotherapy and surgery
Author(s): Chandan Verma[sup.1] , Jennifer M Eremin[sup.2] , Adrian Robins[sup.3] , Andrew J Bennett[sup.4] , Gerard P Cowley[sup.5] , Mohamed A El-Sheemy[sup.2,6] , Jibril A Jibril[sup.2] and Oleg Eremin[sup.1,2] Background [...]