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.

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.

High Treg infiltration correlated with tumor 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 was 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 was associated with a shorter survivial 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 tumor hypoxia, as indicated by CA9 expression (P=0.049).

Our data shows 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-tumor immune response.

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