Prognostic Implications of Tumor-Infiltrating Lymphocytes in Association With Programmed Death Ligand 1 Expression in Early-Stage Breast Cancer

Tumor-infiltrating lymphocytes (TILs) are known to be an important prognostic factor of specific breast cancer subtypes. Among the various regulatory mechanisms, we assessed the associations between programmed death ligand 1 (PD-L1) expression on tumor cells and TILs in early-stage breast cancer according to the hormone receptor (HR) status. A strong positive correlation was found between CD8+ TILs and forkhead box P3-positive TILs and an inverse relationship between TILs and PD-L1 expression. Only in HR-negative tumors were CD8+ TILs associated with better survival. Background: The immune system might influence breast cancer (BC) prognosis. However, the relationship between programmed death ligand 1 (PD-L1) and tumor-infiltrating lymphocyte (TIL) profiles remains unclear with respect to BC subtypes. Patients and Methods: We investigated the relationship between TIL profiles for CD8+ and forkhead box P3 positive (FOXP3+) and PD-L1 expression in primary tumor tissue using immunohistochemistry and the clinical outcomes in 2 patient cohorts at the National Cancer Center: 256 patients diagnosed with early-stage BC from January 2001 to December 2005 and 77 hormone receptor (HR)-negative BC patients diagnosed from January 2006 to December 2008. Clinical data were collected, including HR status, human epidermal growth factor receptor 2 expression, disease-free survival, and overall survival (OS). Results: The median patient age was 47 years (range, 28-78), and the median follow-up period was 9.8 years. Of the 333 patients, 186 (55.9%) had HR-positive and 125 (37.5%) had node-positive BC. We found a strong positive correlation between CD8+ TILs and FOXP3+ TILs (P < .001). CD8+ TILs were more abundant in tumors with low PD-L1 expression (P < .001), although no association was found between FOXP3+ TILs and PD-L1 expression. More CD8+ TILs were present in HR-negative than in HR-positive BC (P < .001), and PD-L1 expression was more frequent in HR-positive BC (P < .001). A greater number of CD8+ TILs (increase in quartile) was strongly associated with OS (hazard ratio, 0.61; 95% confidence interval, 0.39-0.95; P = .03) only in HR-negative BC when adjusted for various clinical factors. PD-L1 expression and FOXP3+ TILs did not exhibit such associations. Conclusion: Higher CD8+ lymphocyte infiltration was related to lower PD-L1 expression and higher FOXP3+ TIL infiltration in BC. Higher CD8+ TIL expression was associated with prolonged survival only in those with HR-negative BC. (C) 2016 Elsevier Inc. All rights reserved.