The ratio of CD8+ lymphocytes to tumor-infiltrating suppressive FOXP3+ effector regulatory T cells is associated with treatment response in invasive breast cancer

Purpose: FOXP3+ tumor-infiltrating lymphocytes (TILs) are prototypical immunosuppressive TILs in breast cancer. However, the FOXP3+ TIL subset of effector regulatory T cells (eTregs) cannot be detected with conventional immunohistochemical staining. Therefore, we evaluate the immunosuppressive potential of eTregs and the role of immunostimulatory CD8+ TILs in invasive breast cancer. Methods: : Fresh TILs were extracted from 84 patients with breast cancer and divided into CD4 + FOXP3 + regulatory T cells (Tregs) and CD8+ cytotoxic T lymphocytes (CTLs) by flow cytometry. Tregs were further classified into eTregs (CD4 + FOXP3 high CD45RA − ), other FOXP3 + Treg subsets (naïve and non-Tregs), and total CD8 + CD4 - TILs.). The association between TILs subpopulation, clinicopathological characteristics, and the response to chemotherapy was evaluated. Results: : The median eTreg proportion among total CD4 + TILs was 18.7% (interquartile range [IQR], 16.4–25.5%), whereas this proportion for CD8 + TILs was 124% (IQR, 87.5–140%). The proportion of eTregs to total FOXP3 + TILs varied widely among patients (median, 65.6%; range, 10.1–93.2%). In an immunosuppression assay with Treg subsets, only eTregs displayed potent immunosuppression. Among the patients who received neoadjuvant chemotherapy (NAC), the pathological complete response(pCR) rate was significantly higher among individuals with a high CD8 + /eTreg ratio (90.2% vs. 33.3%). TILs predominance and CD8/eTreg ratio were independent predictive factors for pCR to chemotherapy ( P = 0.043 and P = 0.034, respectively). Conclusions: : The CD8+/eTreg ratio is a simple, optimal indicator of cancer immunity, and a high CD8+/eTreg ratio may enhance the prognosis and treatment response of patients with invasive breast cancer. Further studies are warranted to validate the present findings.