Histidine decarboxylase-expressing PMN-MDSC-derived TGF-β1 promotes the epithelial-mesenchymal transition of metastatic lung adenocarcinoma.

Abstract

Metastasis is a major risk for lung adenocarcinoma-related mortality. Accumulating evidence raises the possibility that anticancer therapies might be more sensitive by targeting premetastatic niches in addition to the cancer cells themselves. Here, we identified a subpopulation of metastatic lung adenocarcinoma, which was characterized by EMT-related markers such as E-cadherin, Twist, SMAD, and β-catenin. EMT⁺ cases exhibited poorer prognosis than EMT^- patients, reflecting the pro-metastatic features of EMT. Immunohistochemical staining decorated CD15⁺ PMN-MDSCs surrounding EMT⁺ cancer cells in lymph nodes. Metastatic tissues secreted high levels of chemokines, including CXCL1, CXCL5, and CCL2, into the circulation to recruit histidine decarboxylase (Hdc)-positive PMN-MDSCs into metastatic colonies through upregulated CXCR2. The percentage of Hdc⁺ PMN-MDSCs increased in the setting of metastasis. Hdc⁺ PMN-MDSCs obtained from EMT⁺ metastatic masses expressed a higher level of TGF-β1, rather than TGF-β2 and TGF-β3, compared to EMT^- counterparts. The depletion of Hdc⁺ PMN-MDSCs or downregulation of TGF-β1 significantly decreased EMT⁺ percentage and, thus, hampered the metastasis process in murine models. Together, our findings suggest that metastatic tumor secretes high levels of chemokines to recruit Hdc⁺ PMN-MDSCs, which, in turn, express TGF-β1 to induce cancer cells to undergo EMT at metastatic sites.