MMP9 Serves as a Prognostic Biomarker and Immune-Associated Regulator in Diffuse Large B-Cell Lymphoma.

Abstract

Matrix metalloproteinase 9 (MMP9) is a zinc-dependent endopeptidase involved in extracellular matrix (ECM) remodeling and inflammatory signaling. Although MMP9 has been implicated in tumor progression and immune modulation in solid tumors, its clinical relevance and microenvironmental associations in diffuse large B-cell lymphoma (DLBCL) remain incompletely defined. Publicly available transcriptomic and clinical datasets of DLBCL were obtained from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GSE56315). Differential expression and enrichment analyses were performed to characterize biological pathways associated with MMP9 expression. Immune and stromal features were estimated using CIBERSORT, TIMER, and ESTIMATE algorithms. Associations with tumor stemness indices and somatic mutational profiles were explored. In addition, peripheral blood leukocyte profiles were analyzed from an independent cohort of DLBCL patients collected at our institution to assess systemic immune alterations associated with disease status. MMP9 protein expression was further evaluated using immunohistochemical data from the Human Protein Atlas. MMP9 expression was significantly elevated in DLBCL tissues compared with normal lymphoid controls. Higher MMP9 expression was associated with inferior overall survival and increased immune and stromal scores. MMP9 expression correlated with enhanced monocyte and myeloid cell infiltration and enrichment of ECM-related and cytokine-associated signaling pathways, including PI3K-Akt signaling. Analysis of peripheral blood samples revealed altered leukocyte distributions in DLBCL patients, characterized by increased neutrophil and monocyte proportions and reduced lymphocyte fractions, particularly in cases with bone marrow involvement. In addition, MMP9-high tumors exhibited distinct mutational patterns involving genes such as KMT2D and MYD88, along with reduced tumor stemness indices. Immunohistochemical analysis confirmed increased MMP9 protein expression in DLBCL tissues. Elevated MMP9 expression is associated with adverse prognosis and immune-stromal alterations in DLBCL. Integrated transcriptomic, genomic, and clinically derived peripheral blood analyses suggest that MMP9 expression reflects ECM-associated immune remodeling at both local and systemic levels, supporting its potential value as a biomarker linked to the tumor immune microenvironment in lymphoma.