Murine pancreatic adenocarcinoma dampens SHIP-1 expression and alters MDSC homeostasis and function.

摘要: Background Pancreatic cancer is one of the most aggressive cancers, with tumor-induced myeloid-derived suppressor cells (MDSC) contributing to its pathogenesis and ineffective therapies. In response cytokine/chemokine receptor activation, src homology 2 domain-containing inositol 5′-phosphatase-1 (SHIP-1) influences phosphatidylinositol-3-kinase (PI3K) signaling events, which regulate immunohomeostasis. We hypothesize that factors from murine pancreatic cause down-regulation SHIP-1 expression, may potentially contribute MDSC expansion, suppression CD8+ T cell immune responses. Therefore, we sought determine role in solid tumor progression, such as cancer. Methodology Principal Findings Immunocompetent C57BL/6 mice were inoculated either Panc02 (tumor-bearing [TB] mice) or Phosphate Buffer Saline (PBS) (control mice). Cytometric Bead Array (CBA) analysis supernatants cultured detected pro-inflammatory cytokines IL-6, IL-10 MCP-1. TB showed a significant increase serum levels IL-6 MCP-1 measured by CBA. qRT-PCR Western blot analyses revealed vivo expression splenocytes mice. also reduced activity, increased AKT-1 BAD hyper-phosphorylation up-regulation BCL-2 vitro, mRNA protein control co-cultured cells. Flow cytometry results expansion peripheral blood AutoMACS sorted exhibited over-expression western analysis. significantly suppressed antigen-specific responses vitro. Conclusion/Significance SHIP-1 development impacts function, progression. Thus, can be potential therapeutic target help restore immunohomeostasis improve patients cancer.