Targeting gammadelta regulatory T cell recruitment for breast cancer immunotherapy

Immunosuppressive microenvironments induced by regulatory T cells (Treg) present a major barrier for successful anti-tumor immunotherapy. Understanding the mechanisms for the accumulation of different subtypes of Treg cells in the immunosuppressive tumor microenvironment is essential to improving cancer treatment. Enriched gammadelta1 T cell populations in tumor-infiltrating lymphocytes (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 gammadelta Treg cells in breast cancer patients have yet to be elucidated. In this study, we showed that IP-10 secreted by breast cancer cells attracted gammadelta Treg cells. Using neutralizing antibodies against chemokines secreted by breast cancer cells, we found that IP-10 was the only functional chemokine that causes gammadelta Treg cells to migrate toward breast cancer cells. In a humanized NSG mouse model, human breast cancer cells attracted gammadelta Treg cells as revealed by a live cell imaging system. IP-10 neutralization in vivo inhibited migration and trafficking of gammadelta Treg cells into breast tumor sites, enhancing tumor immunity mediated by tumor-specific T cells. Together, our studies show how gammadelta Treg cells accumulate in breast tumors, providing a rationale for their immunological targeting to relieve immunosuppression in the tumor microenvironment.