Prognostic value of tumor infiltrating lymphocyte subsets in breast cancer depends on hormone receptor status

Interaction between immune-regulatory proteins and tumor infiltrating lymphocytes (TILs) is complex, and their associations may have significant clinical implications. This study was designed to evaluate the relationships between immunomodulatory proteins and TIL subsets and their impact on prognosis in breast cancer. 377 invasive breast cancer cases were selected, and immunohistochemistry was performed for HLA-A, HLA-ABC, and indoleamine 2,3-dioxygenase (IDO); CD4+, CD8+, and FOXP3+ T cells were counted in intratumoral and stromal areas for both absolute numbers as well as their ratios. While HLA-ABC and HLA-A expressions showed a positive correlation with CD8+ and FOXP3+ TIL infiltration, IDO expression showed a negative correlation with FOXP3+/CD4+ and FOXP3+/CD8+ T cell ratios. Expressions of HLA-ABC, HLA-A, and IDO shared an association with negative estrogen receptor status. Infiltration of CD4+, CD8+, and FOXP3+ TILs was significantly higher in tumors with high histologic grade, negative hormone receptor status, HER2 amplification, high Ki-67 index, and p53 overexpression. In survival analyses, increased CD4+ TIL infiltration was associated with better prognosis of the patients while other TIL subset infiltration and expression of immunomodulatory proteins had no prognostic significance. In subgroup analyses, high CD4+ TIL infiltration was revealed as an independent good prognostic factor in hormone receptor-negative subgroup while high FOXP3+/CD8+ T cell ratio was found to be an independent adverse prognostic factor in hormone receptor-positive subgroup, especially in luminal A subtype. CD4+ TIL subset and FOXP3+/CD8+ T cell ratio have different prognostic significance in breast cancer according to hormone receptor status.