Tumour-draining axillary lymph nodes in patients with large and locally advanced breast cancers undergoing neoadjuvant chemotherapy (NAC): the crucial contribution of immune cells (effector, regulatory) and cytokines (TH1, TH2) to immune-mediated tumour cell death induced by NAC

Kaewkangsadan, Viriya; Verma, Chandan; Eremin, Jennifer M.; Cowley, Gerard P.; Ilyas, Mohammad; Eremin, Oleg

Abstract

Background

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.

Methods

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.

Results

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.

Conclusions

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.

Citation

Kaewkangsadan, V., Verma, C., Eremin, J. M., Cowley, G. P., Ilyas, M., & Eremin, O. (2018). Tumour-draining axillary lymph nodes in patients with large and locally advanced breast cancers undergoing neoadjuvant chemotherapy (NAC): the crucial contribution of immune cells (effector, regulatory) and cytokines (TH1, TH2) to immune-mediated tumour cell death induced by NAC. BMC Cancer, 18, Article 123. https://doi.org/10.1186/s12885-018-4044-z

• Journal Article Type: Article
• Acceptance Date: Jan 24, 2018
• Online Publication Date: Feb 2, 2018
• Publication Date: Feb 2, 2018
• Deposit Date: May 21, 2016
• Publicly Available Date: Feb 2, 2018
• Journal: BMC Cancer
• Electronic ISSN: 1471-2407
• Publisher: Springer Verlag
• Peer Reviewed: Peer Reviewed
• Volume: 18
• Article Number: 123
• DOI: https://doi.org/10.1186/s12885-018-4044-z
• Keywords: Axillary lymph node; Breast cancer; neoadjuvant chemotherapy; Tumour microenvironment; Tumour-infiltrating lymphocyte subsets; Cytokines.
• Public URL: https://nottingham-repository.worktribe.com/output/908527
• Publisher URL: https://bmccancer.biomedcentral.com/articles/10.1186/s12885-018-4044-z
• Contract Date: May 21, 2016