MMP11 promotes immune escape in esophageal carcinoma cells via the PD-L1/c-MYC signaling pathway

Background: Esophageal cancer (ESCA) is a common malignant tumor in China, with a high incidence and no early symptoms. Surgery and chemotherapy are common clinical treatments, but patients' prognoses have not improved significantly. Immunotherapy has opened a new chapter in the treatment of ESCA in recent years. Although it is known that high MMP11 expression is associated with a variety of tumors and immune microenvironments, the specific mechanisms by which MMP11 regulates cellular immunity remain unknown. In this study, we looked at how MMP11 affects the PD-L1/c-MYC pathway in ESCA cells/tissues. We intended to see if MMP11 interferes with ESCA cell immune escape via the PD-L1/c-MYC pathway, and thus affects ESCA development. Methods: MMP11 expression levels were determined using both the ESCA tumor database and our clinical ESCA sample collection. MMP11 mRNA/protein expression levels in ESCA tissues and cell lines (OE19 and OE33) were determined using RT-qPCR and western blot. The relationship between MMP11 expression levels and overall patient survival was examined using Kaplan-Meier survival curves. ESCA cells' migration ability and apoptosis rate were assessed using wound healing and flow cytometry, respectively. Western blotting was used to identify PD-L1 and c-MYC pathway-related proteins. After co-culture with ESCA knocked down MMP11, flow cytometry was used to determine the proportion of different Treg cells. The content of each cytokine after co-culture was determined using ELISA. In vivo experiments were carried out using a xenograft mouse model. Results: Overexpression of MMP11 was discovered in ESCA tissues and cell lines. MMP11 knockdown reduced PD-L1 expression while inhibiting ESCA cell migration and promoting apoptosis. MMP11 deficiency also resulted in the downregulation of c-MYC pathway-related proteins in ESCA cells. After co-cultivation with Treg cells/PBMCs, ESCA cells in the sh-MMP11 group showed a decrease in the proportion of FoxP3+CD4+-positive cells versus FoxP3 ⁺ CD25 ⁺ -positive cells and an increase in the proportion of FoxP3 ⁺ CD8 ⁺ -positive cells versus the control group (sh-NC). Immunopromoting (TNF-α and IFN-γ) and immunosuppressive (TGF-β and IL-10) factors were elevated and decreased, respectively. Furthermore, animal studies showed that MMP11 knockdown inhibited tumor growth in mice in vivo , suppressed the rate of Ki-67-positive expression, and inhibited the expression of proteins associated with the PD-L1 and c-MYC pathways. Conclusion: MMP11 activates the PD-L1/c-MYC signaling pathway and promotes immune escape of ESCA cells, resulting in the development of ESCA. MMP11-PD-L1/c-MYC may provide a novel approach to ESCA immunotherapy.