Granzyme B Expression in the Tumor Microenvironment as a Prognostic Biomarker for Patients with Triple-Negative Breast Cancer

SIMPLE SUMMARY: Triple-negative breast cancer (TNBC) is generally malignant and has a poor prognosis. New biomarkers and therapeutic strategies are therefore needed. In this study, we investigated whether granzyme B (GZMB) in the tumor microenvironment can be a biomarker of therapeutic response and prognosis in TNBC via the immunohistochemical staining of clinical specimens from 230 patients with primary TNBC. The key results were in the programmed cell death ligand 1 (PD-L1)-positive group, where GZMB-high TNBC patients had better recurrence-free survival and overall survival than GZMB-low patients. A multivariate analysis also showed significantly better overall survival in PD-L1-positive and GZMB-high patients. These results indicate that GZMB is a useful prognostic marker in PD-L1-positive TNBC patients. ABSTRACT: Tumor-infiltrating lymphocytes in the tumor microenvironment are important in the treatment of triple-negative breast cancer (TNBC). Cytotoxic T cells produce cytokines and cytotoxic factors, such as perforin and granzyme, which induce apoptosis by damaging target cells. To identify biomarkers of these cells, we investigated granzyme B (GZMB) in the tumor microenvironment as a biomarker of treatment response and prognosis in 230 patients with primary TNBC who underwent surgery without preoperative chemotherapy between January 2004 and December 2014. Programmed cell death ligand 1 (PD-L1) positivity was defined as a composite positive score ≥10 based on the PD-L1 immunostaining of tumor cells and immune cells. GZMB-high was defined as positivity in ≥1% of tumor-infiltrating lymphocytes (TILs). Among the 230 TNBC patients, 117 (50.9%) had CD8-positive infiltrating tumors. In the PD-L1-positive group, a Kaplan–Meier analysis showed that GZMB-high TNBC patients had better recurrence-free survival (RFS) and overall survival (OS) than GZMB-low patients and that OS was significantly longer (RFS: p = 0.0220, OS: p = 0.0254). A multivariate analysis also showed significantly better OS in PD-L1- and GZMB-high patients (hazard ratio: 0.25 (95% IC: 0.07–0.88), p = 0.03). Our findings indicate that GZMB is a useful prognostic biomarker in PD-L1-positive TNBC patients.