Higher densities of Foxp3+ regulatory T cells are associated with better prognosis in triple-negative breast cancer

The role of Forkhead Box Protein 3 (Foxp3) expressing regulatory T cells (Tregs) in breast cancer remains unclear. We examined the abundance and localisation of total T cells, B cells and Tregs within samples from triple-negative breast cancers (TNBCs) and asked whether these parameters were associated with clinicopathological features of the cancer or clinical outcomes. Samples from TNBCs diagnosed between 2003 and 2010 in Singapore were divided into high and low intra-tumoural or stromal groups, based on whether they had higher or lower than median densities of specific tumour-infiltrating lymphocyte populations (CD3(+) total T cells, Foxp3(+)CD3(+) Tregs, or CD20(+) B cells) in the intra-tumoural space or stroma. Of the 164 samples, patients bearing tumours with high Tregs within their intra-tumoural, but not stromal, areas experienced significantly longer overall and disease-free survival compared to individuals with low Treg densities. These high intra-tumoural Treg tumours were also characterised by relatively higher frequencies of CD8(+) T cells and CD20(+) B cells, and expressed significantly higher levels of some genes associated with inflammation, immune cell functions and trafficking, altogether consistent with a more immune-activated tumour microenvironment, in contrast to tumours bearing lower densities of Tregs. In summary, the combination of high densities of intra-tumoural Tregs, CD8(+) T cells and CD20(+) B cells represents a favourable prognostic panel in TNBCs. These data also indicate new avenues for further investigation on the interaction between immune cell types within the tumour microenvironment and highlight the potential of Treg density and localisation within tumours to affect clinical outcome.