MMP11 Promotes Immune Escape in Esophageal Carcinoma Cells via the PD-L1/c-MYC Signaling Pathway.

Abstract

Background: Esophageal adenocarcinoma (ESCA) remains a highly malignant tumor with poor prognosis, partly due to immune escape mechanisms that promote tumor progression.

Objective: This study aimed to investigate the role of matrix metalloproteinase 11 (MMP11) in regulating the programmed cell death ligand 1 (PD-L1)/cellular MYC (c-MYC) pathway and its effects on immune escape and tumor development in ESCA.

Methods: MMP11 mRNA and protein levels were evaluated in ESCA tissues and cell lines (OE19 and OE33) using real-time quantitative polymerase chain reaction and Western blot analysis. Functional assays, including wound-healing and flow cytometry, were used to assess cell migration and apoptosis, respectively. Co-culture experiments using regulatory T cells and peripheral blood mononuclear cells were performed to analyze the proportions of immune cells. Key cytokines were measured, and a mouse xenograft model was used to validate in vivo effects.

Results: MMP11 expression was significantly upregulated in ESCA tissues and cells. MMP11 knockdown inhibited PD-L1 expression, reduced ESCA cell migration, and promoted apoptosis. Additionally, MMP11 silencing downregulated proteins associated with the c-MYC pathway. Co-culture experiments revealed that MMP11 knockdown reduced the proportions of FoxP3+CD4+ and FoxP3+CD25+ cells while increasing FoxP3+CD8+ cells. Immunopromoting factors, including tumor necrosis factor alpha and interferon gamma, were elevated, whereas immunosuppressive factors, such as transforming growth factor beta and interleukin-10, decreased. In vivo, MMP11 knockdown suppressed tumor growth and reduced the expression of Ki-67, PD-L1, and c-MYC pathway proteins.

Conclusion: MMP11 promotes ESCA progression by activating the PD-L1/c-MYC pathway and facilitating immune escape. Targeting MMP11 may enhance immunotherapeutic strategies for ESCA.