Infiltrating Myeloid Cells Exert Pro-Tumorigenic Actions via Neutrophil Elastase

摘要

Tissue infiltration and elevated peripheral circulation of granulocytic myeloid-derived cells is associated with poor outcomes in prostate cancer (PCa) and other malignancies. Although myeloid-derived cells have the ability to suppress T-cell function, little is known about the direct impact of these innate cells on prostate tumor growth. Here it is reported that granulocytic myeloid-derived suppressor cells (MDSCs) are the predominant tumor infiltrating cells in PCa xenografts established in athymic nude mice. MDSCs significantly increased in number in the peripheral circulation as a function of xenograft growth and were successfully depleted in vivo by Gr-1 antibody treatment. Importantly, MDSC depletion significantly decreased xenograft growth. We hypothesized that granulocytic MDSCs might exert their pro-tumorigenic actions in part through neutrophil elastase (ELA2/NE), a serine protease released upon granulocyte activation. Indeed, it was determined that NE is expressed by infiltrating immune cells and is enzymatically active in PCa xenografts and in prostate tumors of prostate-specific Pten-null mice. Importantly, treatment with sivelestat, a small-molecule inhibitor specific for NE, significantly decreased xenograft growth, recapitulating the phenotype of Gr-1 MDSC depletion. Mechanistically, NE activated mitogen-activated protein kinase (MAPK) signaling and induced MAPK-dependent transcription of the proliferative gene cFOS in PCa cells. Functionally, NE stimulated proliferation, migration, and invasion of PCa cells in vitro. Immunohistochemistry (IHC) on human PCa clinical biopsies revealed co-expression of NE and infiltrating CD33+ MDSCs.