Specific Recruitment of γδ 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 gamma delta 1 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 (gamma delta 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 gamma delta Tregs. Using neutralizing antibodies against chemokines secreted by breast cancer cells, we found that IP-10 was the only functional chemokine that causes gamma delta Tregs to migrate toward breast cancer cells. In a humanized NOD-scid IL-2R gamma(null) (NSG) mouse model, human breast cancer cells attracted gamma delta Tregs as revealed by a live cell imaging system. IP-10 neutralization in vivo inhibited migration and trafficking of gamma delta Tregs into breast tumor sites, enhancing tumor immunity mediated by tumor-specific T cells. Together, our studies show how gamma delta Tregs accumulate in breast tumors, providing a rationale for their immunologic targeting to relieve immunosuppression in the tumor microenvironment. Cancer Res; 73(20); 6137-48. (C) 2013 AACR.