Immune Sculpting of Norepinephrine on MHC-I, B7-1, IDO and B7-H1 Expression and Regulation of Proliferation and Invasion in Pancreatic Carcinoma Cells

Abstract

BackgroundThe sympathetic neurotransmitter Norepinephrine (NE) contributes to tumorigenesis and cancer progression. This study aims to investigate the role of NE in modulating the immune phenotype and allowing pancreatic carcinoma (PC) cells to escape the immune response.MethodsVaried concentrations of NE and interferon-gamma (IFN-γ) were administrated to MIA PaCa-2 and BxPC-3 cell lines for 48 hours. Proliferation and invasion were then investigated using an MTT assay and a membrane invasion culture system respectively. MHC-I, B7-1, IDO and B7-H1 expression were measured using real-time quantitative RT-PCR, western blotting and immunocytochemistry. The synergistic and time-dependent effects of NE/IFN-γ were also investigated. Adrenergic antagonists were used to identify the relevant target receptor of NE.ResultsThe results showed that NE had dose-dependent and time-dependent effects on cell biological processes as well as on the expression of MHC-I, B7-1, IDO and B7-H1. These effects occurred mainly via the β2-adrenergic receptor. Long-term NE treatment was able to antagonize some of the effects of IFN-γ (after 2 weeks of treatment), but NE and IFN-γ had significant synergistic stimulatory effects on IDO and B7-H1 expression. The residual effects on biological activities lasted for 2 weeks, while the immunophenotypic changes decreased at early time points after treatment.ConclusionsNE plays important roles in modulating PC cell biological activities and affecting MHC-I, B7-1, IDO and B7-H1 expression in vitro, mainly via the β2-adrenergic receptor (β2-AR) in a time- and dose-dependent fashion. Only at extended treatment durations could NE affect PC cell progression and immune evasion.

B7-H1 Expression Is Associated with Poor Prognosis in Colorectal Carcinoma and Regulates the Proliferation and Invasion of HCT116 Colorectal Cancer Cells

“…B7-H1 has been previously shown to regulate cell migration and invasion in pancreatic carcinoma cells [27]. Our observations that B7-H1 expression played an important role in HCT116 cell proliferation and apoptosis led us to assess the function of B7-H1 on cell migration and invasion in colon cancer cells.…”

“…Though some research groups have confirmed that tumor cells expressing B7-H1 had a high proliferative index [14,27], most groups tended to believe B7-H1 prevent tumor destruction only by forming “a molecular shield [18,29]” but not forming “a more powerful spear” [18,30]. Our finding provides powerful evidence that B7-H1 may have oncogenic function during colonic carcinogenesis, which shed a new light on the function of B7-H1 in colorectal cancer development.…”

Housing temperature-induced stress drives therapeutic resistance in murine tumour models through β2-adrenergic receptor activation

“…Furthermore, recent reports have demonstrated that NE can act as a pro-survival signal to tumour cells leading to increased metastasis, growth and diminished therapeutic response 49–54 . We hypothesized that mild sub-thermoneutral housing temperatures could elicit a sympathetic cold stress response that would increase levels of NE, which would activate pro-survival pathways in these tumours by binding to β-adrenergic receptors.…”

A nervous tumor microenvironment: the impact of adrenergic stress on cancer cells, immunosuppression, and immunotherapeutic response

“…One study observed that pancreatic tumor cells exposed to NE had decreased expression of MHC class I molecules as well as the co-stimulatory ligand B7-1, and increased levels of immunosuppressive indolamine-2,3-oxygenase (IDO) and B7H-1 (PD-L1), the ligand for the programmed cell death receptor (PD-1). While these changes only persisted for a short period of time, these phenotypic changes on cancer cells would not only prevent T cell recognition, but also impair their function by depleting essential nutrients such as tryptophan (by IDO) and inducing exhaustion even in activated lymphocytes [91]. …”