Tumor-Infiltrating γδ T Lymphocytes Predict Clinical Outcome in Human Breast Cancer

Understanding and dissecting the role of different subsets of regulatory tumor-infiltrating lymphocytes (TILs) in the immunopathogenesis of individual cancer is a challenge for anti-tumor immunotherapy. High levels of gamma delta regulatory T cells have been discovered in breast TILs. However, the clinical relevance of these intratumoral gamma delta T cells is unknown. In this study, gamma delta T cell populations were analyzed by performing immunohistochemical staining in primary breast cancer tissues from patients with different stages of cancer progression. Retrospective multivariate analyses of the correlations between gamma delta T cell levels and other prognostic factors and clinical outcomes were completed. We found that gamma delta T cell infiltration and accumulation in breast tumor sites was a general feature in breast cancer patients. Intratumoral gamma delta T cell numbers were positively correlated with advanced tumor stages, HER2 expression status, and high lymph node metastasis but inversely correlated with relapse-free survival and overall survival of breast cancer patients. Multivariate and univariate analyses of tumor-infiltrating gamma delta T cells and other prognostic factors further suggested that intratumoral gamma delta T cells represented the most significant independent prognostic factor for assessing severity of breast cancer compared with the other known factors. Intratumoral gamma delta T cells were positively correlated with FOXP3(+) cells and CD4(+) T cells but negatively correlated with CD8(+) T cells in breast cancer tissues. These findings suggest that intratumoral gamma delta T cells may serve as a valuable and independent prognostic biomarker, as well as a potential therapeutic target for human breast cancer. The Journal of Immunology, 2012, 189: 5029-5036.