Specific Recruitment of gd Regulatory T Cells in Human Breast Cancer

Understanding the role of different subtypes of tumor-infiltrating lymphocytes (TIL) in the immunosuppressive tumor microenvironment is essential for improving cancer treatment. Enriched gd1 T-cell populations in TILs suppress T-cell responses and dendritic cell maturation in breast cancer, where their presence is correlated negatively with clinical outcomes. However, mechanism(s) that explain the increase in this class of regulatory T cells (gd Treg) in patients with breast cancer have yet to be elucidated. In this study, we show that IP-10 secreted by breast cancer cells attracted gd Tregs. Using neutralizing antibodies against chemokines secreted by breast cancer cells, we found that IP-10 was the only functional chemokine that causes gd Tregs to migrate toward breast cancer cells. In a humanized NOD-scid IL-2Rg (NSG) mouse model, human breast cancer cells attracted gd Tregs as revealed by a live cell imaging system. IP-10 neutralization in vivo inhibited migration and trafficking of gd Tregs into breast tumor sites, enhancing tumor immunity mediated by tumor-specific T cells. Together, our studies show how gd Tregs accumulate in breast tumors, providing a rationale for their immunologic targeting to relieve immunosuppression in the tumor microenvironment. Cancer Res; 73(20); 1–12. 2013 AACR.