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

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

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.

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.

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.

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