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

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.

Exploring GZMK as a prognostic marker and predictor of immunotherapy response in breast cancer: unveiling novel insights into treatment outcomes

“…In studies related to GZMB, it was observed that in the PD-L1-positive group, Kaplan–Meier analysis revealed better recurrence-free survival (RFS) and OS in triple-negative breast cancer (TNBC) patients with high expression of GZMB (defined as ≥ 1% tumor-infiltrating lymphocytes (TILs) positive). Both RFS and OS were significantly prolonged in patients with high GZMB expression (RFS: P = 0.0220, OS: P = 0.0254) (Mizoguchi et al 2023 ). Multivariable Cox analysis also indicated better OS in patients with high expressions of PD-L1 and GZMB (hazard ratio: 0.25 (95% CI: 0.07–0.88), P = 0.03), suggesting that GZMB is a useful prognostic biomarker for PD-L1-positive TNBC patients (Mizoguchi et al 2023 ).…”

“…Both RFS and OS were significantly prolonged in patients with high GZMB expression (RFS: P = 0.0220, OS: P = 0.0254) (Mizoguchi et al 2023 ). Multivariable Cox analysis also indicated better OS in patients with high expressions of PD-L1 and GZMB (hazard ratio: 0.25 (95% CI: 0.07–0.88), P = 0.03), suggesting that GZMB is a useful prognostic biomarker for PD-L1-positive TNBC patients (Mizoguchi et al 2023 ). Additionally, a study found that high expression of GZMK in advanced melanoma significantly improved patients' PFS and OS (PFS: P = 0.04, OS: P = 0.01) (Wu et al 2021b ).…”

Spatial proteomic profiling of tumor and stromal compartments in non‐small‐cell lung cancer identifies signatures associated with overall survival

“…It has been shown that high GZMB is associated with the increased cytotoxic activity of tumor‐infiltrating lymphocytes (TILs) and improved disease‐free survival (DFS) and OS in multiple cancer types. 62 , 63 However, GZMB expression alone or coupled with markers like PD‐L1 can variably affect both recurrence‐free survival (RFS) and OS. 62 , 64 , 65 Our study supports these contradictory data by demonstrating that high GZMB expression is linked with poor survival.…”

“… 62 , 63 However, GZMB expression alone or coupled with markers like PD‐L1 can variably affect both recurrence‐free survival (RFS) and OS. 62 , 64 , 65 Our study supports these contradictory data by demonstrating that high GZMB expression is linked with poor survival. It implies that the impact of cytotoxic activity may vary depending on the cancer type and immunological context.…”