The tumor-infiltrating effector regulatory T cell:CD8+ lymphocyte ratio in invasive breast cancer
Abstract Background Tumor-infiltrating lymphocytes (TILs) in breast cancer comprise immunostimulating and immunosuppressive components. Although FOXP3+ TILs are prototypical immunosuppressive TILs, only effector regulatory T cells (eTreg), a subset of immunosuppressive FOXP3+ TILs, are undetectable on immunohistochemical staining. This study aimed to evaluate the immunosuppressive potential of eTregs and the role of prototypical immunostimulatory CD8+ TILs in invasive breast cancer. Methods Fresh TILs extracted from 84 invasive breast cancer patients were analyzed via flow cytometry. We evaluated eTregs (CD4+FOXP3highCD45RA−), other FOXP3+ Treg subsets (naïve and non-Tregs), and total CD8+CD4- TILs. Clinicopathological factors, including histopathological characteristics, were also assessed. Results The median eTreg proportion of the total CD4+TILs was 18.7% (interquartile range [IQR], 16.4–25.5%); CD8+TILs, 124% (IQR, 87.5–140%). The proportion of eTregs to total FOXP3+ TILs varied (median, 65.6%; range, 10.1–93.2%). In an immunosuppression assay, only eTregs displayed potent immunosuppression; however, other Treg subsets did not. Among 39 patients who received neoadjuvant chemotherapy, eTreg subsets and pathological compete response (pCR) did not differ significantly, while pCR rates were significantly higher among individuals with a high than those with a low CD8+/eTreg ratio (90.2% vs 33.3%; P<0.05). Among all patients, a high CD8+/eTreg ratio tended to be associated with better disease-free survival rather than a low CD8+/eTreg ratio (P=0.09). Conclusions The CD8+/eTreg ratio is simple, optimal indicator of cancer immunity, and a high CD8+/eTreg ratio enhances the prognosis and treatment response in invasive breast cancer patients. However, further studies are required to validate the present findings.
