Ex vivoNicotine Stimulation Augments the Efficacy of Therapeutic Bone Marrow–Derived Dendritic Cell Vaccination

Abstract

Purpose: To explore the preventive and therapeutic antitumor effects of nicotine-treated immature dendritic cells (imDC). Experimental Design: First, bone marrow^derived imDCs were stimulated with nicotine in vitro, and nicotinic acetylcholine receptor, costimulator molecules, chemokine receptor, and endocytosis ability of imDCs were detected by flow cytometry. Second, the DC-dependent antigen-specific T-cell proliferation, CTL priming, and interleukin-12 secretion were determined by flow cytometry, enzyme-linked immunospot assay, and ELISA, respectively. Finally, preventive and therapeutic antitumor effects of such imDCs were determined by i.p. transfer against tumor challenge or implantation in mice. Results: Nicotine could up-regulate expression of nicotinic acetylcholine receptor, costimulatory molecules, such as CD80, CD86, and CD40, adhesion molecule CD11b, and chemokine receptor CCR7 and enhance endocytosis ability of imDCs. In addition, nicotine could promote imDCdependent CTL priming and interleukin-12 secretion in vitro. Most importantly, systemic transfer of ex vivo nicotine-stimulated imDCs could reveal preventive and therapeutic effect on tumor development. Conclusions: Ex vivo nicotine stimulation can significantly improve the efficacy of imDCs for adaptive therapy of cancer and nicotine-treated imDCs may be considered as a potential candidate for preventive and therapeutic tumor vaccination.Numerous approaches for antigen-specific active immunotherapy have been developed relying on random encounter of the vaccine with host dendritic cells (DC; refs. 1, 2). A lack of encounter of the vaccine antigen with DCs might result in the absence of an immune response, or alternatively, an inappropriate encounter might lead to silencing of the immune response (3). Therefore, studies are urgently needed based on ex vivo -generated autologous DCs loaded with antigen under controlled conditions. Some reports have shown that DCs loaded with antigens could induce therapeutic and protective antitumor immunity in mice (3, 4). But, the efficacy of therapeutic vaccination has been questioned recently (5). In the last decade, several groups have documents that nicotine has positive effects in treatment of neurodegenerative diseases, ulcerative colitis and, Tourette syndrome (6 -8). Although the expression of nicotinic acetylcholine receptor (nAChR) has been shown in many types of nonneuronal cells, such as DCs, epithelial cells, and endothelial cells (9), the effect of nicotine on immune cells is incompletely characterized. Some investigators showed that nicotine could promote immune cell activation (10 -12), whereas others indicated that nicotine might have immunosuppressive effects on macrophages and DCs (13 -15). In the present study, we first characterized that nicotine has stimulatory effects on immature DCs (imDC) and second showed that nicotine stimulation could enhance T-cell priming ability of imDCs. Finally and most importantly, we revealed the in vivo preventive and therapeutic effect on tumor devel...

Nicotine and inflammatory neurological disorders

“…In a recent study, it has also been reported that nicotine could up-regulate expression of nicotinic acetylcholine receptors, costimulatory molecules (such as CD80, CD86), CD40, CD11b, and chemokine receptor, CCR7 [28,29] . Nicotine could also enhance the endocytotic ability of imDCs in addition to possibly promoting imDC dependent CTL priming and IL-12 secretion in vitro [28,29,58] . Nicotine effects on the immune system in vivo Increasing evidence has shown that nicotine exerts its effects on the immune system in vivo.…”

Tumor necrosis factor α-induced protein 8-like 1 promotes apoptosis by regulating B-cell leukemia/lymphoma-2 family proteins in RAW264.7 cells

“…Tumor implantation experiments were conducted as described previously (12). Briefly, every mouse was challenged with 2x10 6 RAW264.7-TIPE1 or RAW264.7-MigR1 cells through subcutaneous injection in the back.…”

Nicotine stimulated bone marrow-derived dendritic cells could augment HBV specific CTL priming by activating PI3K-Akt pathway

“…Bone marrow-derived DCs were prepared as previously described [22]. Briefly, bone marrow cells were cultured in RPMI medium supplemented with 10% FBS at the presence of 10 ng/ml GM-CSF and 1 ng/ml IL-4.…”

“…Moreover, nicotine upregulates costimulatory molecules such as CD86 and CD40, MHC class molecules such as HLA-DR, and adhesion molecules such as CD54 and enhances adaptive immunity, an effect that is mediated by nicotinic ACh receptors on human DCs and monocytes [21]. Our previous studies demonstrated that nicotine had stimulatory effects on murine immature DCs (imDCs), enhanced DCs-mediated CTL priming and facilitated the preventive and therapeutic effects on lymphoma [22], Lewis lung cancer and hepatocellular carcinoma [23]. As HBV antigen pulsed DCs can efficiently augment HBV-specific CTL response in chronically infected HBV patients and HBV transgenic mice [24][25][26], the roles of nicotine-treated DCs in HBV immunotherapy still need to be determined.…”