HLA-DR Regulates Macrophage Phenotypic Transformation and Affects Malignant Behavior in Esophageal Squamous Cell Carcinoma

Abstract

Background Tumor-associated macrophages (TAMs) are an important immune cell component of the tumor microenvironment. This study aimed to explore the molecular mechanism of TAMs phenotype transformation and the role in the development of esophageal squamous cell carcinoma (ESCC). Methods Co-culture conditions were employed to determine the phenotypic effects of TAMs on ESCC cell biological behavior. Tumor metastasis related molecules VEGF-C and MMP-9 produced by TAMs was evaluated by qRT-PCR and western blot. Expression of HLA-DR was knocked down in TAMs in vitro to determine the effects on macrophage polarization and the biological behavior of ESCC. We determined whether co-injection with M2 TAMs and macrophages depletion affected tumor growth in vivo tumor challenge model. Associations between HLA-DR, TAM density, and clinical outcomes were evaluated in patients with ESCC. Results TAMs in ESCC samples were found to closely re ect the M2 phenotype of TAMs, and exhibited low expression of HLA-DR. Which was involved in ESCC tumor invasion and metastasis. Low expression of HLA-DR positively correlated with high-density of M2 TAMs, indicating high invasiveness and poor prognosis in patients with ESCC. Downregulation of HLA-DR in TAMs led to additional M2-type TAM polarization and more VEGF-C and MMP-9 secretion, promoted the malignant transformation of ESCC. Conclusions These results demonstrate that downregulation of HLA-DR promote the transformation of M2 TAMs, and participate in the invasion and metastasis of ESCC.

The Human Myofibroblast Marker Xylosyltransferase-I: A New Indicator for Macrophage Polarization

“…Furthermore, our results showed more pronounced M1-like marker HLA-DR, CD80 and IL-6 expressions of M1 M-MΦ compared to those of M0 and M2 M-MΦ cultures, and were also in line with data reported from the literature. In addition, we observed a negative correlation of HLA-DR expression with that of CD163 in our cell culture model, which is in close agreement with the literature of tumor-associated macrophages [ 48 ]. It is noteworthy that we did not find CD163 upregulation in M2 M-MΦ compared to the other M-MΦ subtypes, although CD163 was defined as a surface marker for M2-like cells [ 33 ].…”