Exogenous HMGB1 promotes pancreatic cancer progression by supporting the crosstalk between tumor and myeloid-derived suppressor cell

Abstract

Background The main reasons pancreatic cancer (PC) is difficult to treat are high tissue fibrosis and a strong immunosuppressive microenvironment. Therefore, it is necessary to elucidate the cause and mechanism of tumour immunosuppressive microenvironment formation. High-mobility group Box 1 (HMGB1) is a highly conserved nuclear protein that is widely distributed in mammalian cells and plays an important role in tumours. However, the functions and mechanisms of HMGB1 in the PC tumour microenvironment remain controversial. Here, we report a novel role for HMGB1 in the formation of the PC immune microenvironment. Methods In this study, the HMGB1 expression level of samples was detected in PC patients and TCGA database. The relative expression of HMGB1 in serum and tissues was evaluated by enzyme-linked immunosorbent assay (ELISA). Flow cytometry was used to detect the infiltration of myeloid-derived suppressor cells (MDSCs) and regulatory T cells in tumours from PC xenograft mouse models treated with HMGB1. Vascular density and cytokine expression levels in tumour tissues were measured by immunohistochemistry (IHC). HMGB1-associated differentially expressed genes from the GEPIA database were used to analyse GO terms and KEGG pathways. Subsequently, the expression of related proteins was detected by Western blotting. Results The expression level of HMGB1 was higher in PC tumours than in normal tissues. High levels of HMGB1 predict poor overall survival in PC patients, suggesting its potential clinical significance in PC prognosis. The mouse model results show that HMGB1 significantly promotes tumour growth. We further found that CD69+CD8+ T cells were markedly decreased in HMGB1-treated mice. Furthermore, after treatment with HMGB1, the infiltration of immunosuppressive myeloid-derived suppressor cells (MDSCs) into tumour tissues was increased. The IHC results showed that HMGB1 promoted the expression of intracellular inflammatory factors and neovascularization. Mechanistically, the results indicated that HMGB1 significantly enhanced the expression of CXCL2 chemokines that attract MDSCs to tumours. HMGB1 upregulates CXCL2 expression through the MAPK pathway. Conclusion In conclusion, HMGB1 plays an unexpected role in cancer metastasis by promoting microvessel formation and cytokine CXCL2 expression mediated by the MAPK pathway to recruit MDSC aggregation, which in turn creates an immunosuppressive microenvironment. Thus, HMGB1 may be an important mediator and a potential therapeutic target for regulating PC progression.