Research article
Recruitment of regulatory T cells is correlated with hypoxia-induced CXCR4 expression, and is associated with poor prognosis in basal-like breast cancers
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* Corresponding author: Max Yan max.yan@sesiahs.health.nsw.gov.au
1 Department of Pathology, Peter MacCallum Cancer Centre, St Andrews Place, East Melbourne, Melbourne, VIC 3002, Australia
2 Cancer Research Program, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, Sydney, NSW 2010, Australia
3 School of Medical Sciences, University of New South Wales, High Street, Kensington, Sydney, NSW 2052, Australia
4 South East Area Laboratory Services, St George Hospital, South Street, Kogarah, Sydney, 2217, Australia
5 School of Medicine, University of Western Sydney, Narellan Road, Campbelltown, Sydney, NSW 2560, Australia
6 Department of Tissue Pathology, Royal Prince Alfred Hospital, Missenden Road, Camperdown, Sydney, NSW 2010, Australia
7 Department of Medical Oncology, Royal Prince Alfred Hospital, Missenden Road, Camperdown, Sydney, NSW 2010 Australia
8 Nuffield Department of Clinical Laboratory Sciences and Medical Oncology, University of Oxford, Henry Wellcome Building for Molecular Physiology, Old Road Campus, Headington, Oxford, OX3 7BN, UK
9 Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DS, UK
Breast Cancer Research 2011, 13:R47 doi:10.1186/bcr2869
Published: 26 April 2011Abstract
Introduction
Basal-like breast cancers behave more aggressively despite the presence of a dense lymphoid infiltrate. We hypothesised that immune suppression in this subtype may be due to T regulatory cells (Treg) recruitment driven by hypoxia-induced up-regulation of CXCR4 in Treg.
Methods
Immunoperoxidase staining for FOXP3 and CXCL12 was performed on tissue microarrays from 491 breast cancers. The hypoxia-associated marker carbonic anhydrase IX (CA9) and double FOXP3/CXCR4 staining were performed on sections from a subset of these cancers including 10 basal-like and 11 luminal cancers matched for tumour grade.
Results
High Treg infiltration correlated with tumour CXCL12 positivity (OR 1.89, 95% CI 1.22 to 2.94, P = 0.004) and basal phenotype (OR 3.14, 95% CI 1.08 to 9.17, P = 0.004) in univariate and multivariate analyses. CXCL12 positivity correlated with improved survival (P = 0.005), whereas high Treg correlated with shorter survival for all breast cancers (P = 0.001), luminal cancers (P < 0.001) and basal-like cancers (P = 0.040) that were confirmed in a multivariate analysis (OR 1.61, 95% CI 1.02 to 2.53, P = 0.042). In patients treated with hormone therapy, high Treg were associated with a shorter survival in a multivariate analysis (OR 1.78, 95% CI 1.01 to 3.15, P = 0.040). There was a tendency for luminal cancers to show CXCL12 expression (102/138, 74%) compared to basal-like cancers (16/27, 59%), which verged on statistical significance (P = 0.050). Up-regulation of CXCR4 in Treg correlated with the basal-like phenotype (P = 0.029) and tumour hypoxia, as indicated by CA9 expression (P = 0.049).
Conclusions
Our data show that in the setting of hypoxia and CXCR4 up-regulation in Treg, CXCL12 expression may have the negative consequence of enhancing Treg recruitment and suppressing the anti-tumour immune response.