FOXP3+ Tregs and B7-HI+/PD-I+T lymphocytes co-infiltrate the tumor tissues of high-risk breast cancer patients:: Implication for immunotherapy

Background: Recent studies have demonstrated a direct involvement of B7-H1, PD-1 and FOXP3 molecules in the immune escape of cancer. B7-H1 is an inhibitory molecule that binds to PD-1 on T lymphocytes, while FOXP3 is a marker for regulatory T cells (T-regs). We have previously demonstrated the association of B7-H1-expressing T infiltrating lymphocytes (TIL) with high-risk breast cancer patients while other studies reported the involvement of FOXP3+ T-regs as a bad prognostic factor in breast tumors. Although the co-existence between the two types of cells has been demonstrated in vitro and animal models, their relative infiltration and correlation with the clinicopathological parameters of cancer patients have not been well studied. Therefore, we investigated TIL-expressing the B7-H1, PD-1, and FOXP3 molecules, in the microenvironment of human breast tumors and their possible association with the progression of the disease. Methods: Using immunohistochemistry, tumor sections from 62 breast cancer patients were co-stained for B7-H1, PD-1 and FOXP3 molecules and their expression was statistically correlated with factors known to be involved in the progression of the disease. Results: A co-existence of B7-H1+T lymphocytes and FOXP3(+) T-regs was evidenced by the highly significant correlation of these molecules (P<.0001) and their expression by different T lymphocyte subsets was clearly demonstrated. Interestingly, concomitant presence of FOXP3(+) T-regs, B7-H1+ and PD-1+TIL synergistically correlated with high histological grade (III) (P <.001), estrogen receptor negative status (P = .017), and the presence of severe lymphocytic infiltration (P = .022). Conclusion: Accumulation of TIL-expressing such inhibitory molecules may deteriorate the immunity of high-risk breast cancer patients and this should encourage vigorous combinatorial immunotherapeutic approaches targeting T-regs and B7-H1/PD-1 molecules.