Division of Gastrointestinal Surgery, Nottingham Digestive Diseases Centre, Faculty of Medicine and Health Sciences, University of Nottingham, E Floor West Block, Queen's Medical Centre, Derby Rd, Nottingham, NG7 2UH, UK.
Department of Surgery, Phramongkutklao Hospital and College of Medicine, 315 Rajavithi Road, Bangkok, 10400, Thailand.
BMC Cancer. 2018 Feb 2;18(1):123. doi: 10.1186/s12885-018-4044-z.
The tumour microenvironment consists of malignant cells, stroma and immune cells. In women with large and locally advanced breast cancers (LLABCs) undergoing neoadjuvant chemotherapy (NAC), tumour-infiltrating lymphocytes (TILs), various subsets (effector, regulatory) and cytokines in the primary tumour play a key role in the induction of tumour cell death and a pathological complete response (pCR) with NAC. Their contribution to a pCR in nodal metastases, however, is poorly studied and was investigated.
Axillary lymph nodes (ALNs) (24 with and 9 without metastases) from women with LLABCs undergoing NAC were immunohistochemically assessed for TILs, T effector and regulatory cell subsets, NK cells and cytokine expression using labelled antibodies, employing established semi-quantitative methods. IBM SPSS statistical package (21v) was used. Non-parametric (paired and unpaired) statistical analyses were performed. Univariate and multivariate regression analyses were carried out to establish the prediction of a pCR and Spearman's Correlation Coefficient was used to determine the correlation of immune cell infiltrates in ALN metastatic and primary breast tumours.
In ALN metastases high levels of TILs, CD4 and CD8 T and CD56 NK cells were significantly associated with pCRs.. Significantly higher levels of Tregs (FOXP3, CTLA-4) and CD56 NK cells were documented in ALN metastases than in the corresponding primary breast tumours. CD8 T and CD56 NK cells showed a positive correlation between metastatic and primary tumours. A high % CD8 and low % FOXP3 T cells and high CD8: FOXP3 ratio in metastatic ALNs (tumour-free para-cortex) were associated with pCRs. Metastatic ALNs expressed high IL-10, low IL-2 and IFN-ϒ.
Our study has provided new data characterising the possible contribution of T effector and regulatory cells and NK cells and T helper1 and 2 cytokines to tumour cell death associated with NAC in ALNs.
The Trial was retrospectively registered. Study Registration Number is ISRCTN00407556 .
肿瘤微环境由恶性细胞、基质和免疫细胞组成。在接受新辅助化疗（NAC）的大且局部晚期乳腺癌（LLABC）女性中，原发性肿瘤中的肿瘤浸润淋巴细胞（TIL）、各种亚群（效应、调节）和细胞因子在诱导肿瘤细胞死亡和 NAC 的病理完全缓解（pCR）方面发挥着关键作用。然而，它们对淋巴结转移中 pCR 的贡献研究甚少。
对接受 NAC 的 LLABC 女性的腋窝淋巴结（ALN）（24 个有转移，9 个无转移）进行免疫组织化学评估，使用标记抗体检测 TIL、T 效应和调节细胞亚群、NK 细胞和细胞因子的表达，采用已建立的半定量方法。使用 IBM SPSS 统计软件包（21v）。采用非参数（配对和非配对）统计分析。进行单变量和多变量回归分析以确定 pCR 的预测，并使用 Spearman 相关系数确定 ALN 转移性和原发性乳腺癌中免疫细胞浸润的相关性。
在 ALN 转移中，TIL、CD4 和 CD8 T 以及 CD56 NK 细胞的高水平与 pCR 显著相关。在 ALN 转移中，Tregs（FOXP3、CTLA-4）和 CD56 NK 细胞的水平明显高于相应的原发性乳腺癌。CD8 T 和 CD56 NK 细胞在转移性和原发性肿瘤之间呈正相关。转移性 ALN 中高比例的 CD8 和低比例的 FOXP3 T 细胞以及高 CD8：FOXP3 比值与 pCR 相关。转移性 ALN 表达高 IL-10、低 IL-2 和 IFN-γ。
我们的研究提供了新的数据，这些数据描述了 T 效应和调节细胞、NK 细胞以及辅助性 T 细胞 1 和 2 细胞因子在与 NAC 相关的 ALN 中肿瘤细胞死亡中的可能贡献。
该试验是回顾性注册的。研究注册号为 ISRCTN00407556。
