title: Characterisation of tumour-infiltrating macrophages: impact on response and survival in patients receiving primary chemotherapy for breast cancer.
abstract: The role of the tumour microenvironment and complex cellular interactions has attracted interest in responses to primary chemotherapy. Of particular interest are tumour-infiltrating T cells and tumour-infiltrating macrophages (TIMs). We evaluated TIMs and their key activation markers in patients with breast cancer undergoing primary chemotherapy related to response and survival. One hundred and ninety nine patients with large or locally advanced breast cancers received primary chemotherapy. Clinical data, histopathological responses to chemotherapy and survival were examined related to infiltrating cells in tumour microenvironments: cluster of differentiation (CD)3 (pan T cell); CD4 (helper T cells); CD8 (cytotoxic T cells); CD25 (activated T cells); CD68, suppressor of cytokine signalling (SOCS)1, SOCS3 (macrophages); and CD11c and CD205 (dendritic). In tumours demonstrating better responses to chemotherapy, there were significantly fewer CD4(+) T-helper cells than a poorer response (p < 0.05). There were increased numbers of SOCS3 expressing macrophages (pro-inflammatory) in tumours with complete pathological responses compared with no response to chemotherapy (p < 0.05). There was no association between SOCS1 expressing macrophages (anti-inflammatory) and tumour response. Multivariate analysis revealed that factors indicating better survival were receiving anthracycline plus docetaxel (ExpB = 1.166; p = 0.006), better pathological chemotherapy response (ExpB = 0.309; p = 0.009) and a low macrophage SOCS1 expression (ExpB = 13.465; p = 0.044). This study highlights the heterogeneity of TIMs and provides further insight into complex interactions within tumours. The results emphasise the importance of characterising activation status of infiltrating macrophages and provides proof of principle for using macrophage SOCS protein expression as a survival predictor. The apparent impact of macrophage subsets on overall survival underlines the therapeutic potential of manipulating macrophage activation in cancer.
authors.affiliation: Division of Applied Medicine, School of Medicine and Dentistry, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, Scotland, UK. s.d.heys@abdn.ac.uk
authors.forename: Steven D
authors.initials: SD
authors.lastname: Heys
authors.forename: Keith N
authors.initials: KN
authors.lastname: Stewart
authors.forename: Emma J
authors.initials: EJ
authors.lastname: McKenzie
authors.forename: Iain D
authors.initials: ID
authors.lastname: Miller
authors.forename: Simon Y C
authors.initials: SY
authors.lastname: Wong
authors.forename: Grant
authors.initials: G
authors.lastname: Sellar
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Rees
mesh_terms: D000328:Adult; D000368:Aged; D018943:Anthracyclines / Q000008:administration & dosage; D015703:Antigens, CD / Q000378:metabolism; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology* / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology*; D018270:Carcinoma, Ductal, Breast / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology*; D002986:Clinical Trials as Topic; D003713:Dendritic Cells / Q000378:metabolism / Q000473:pathology; D000077143:Docetaxel; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008264:Macrophages / Q000378:metabolism / Q000473:pathology*; D008875:Middle Aged; D015999:Multivariate Analysis; D013601:T-Lymphocytes / Q000378:metabolism / Q000473:pathology; D043823:Taxoids / Q000008:administration & dosage; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D018943:Anthracyclines; D015703:Antigens, CD; D043823:Taxoids; D000077143:Docetaxel