CD26/DPP4-inhibition suppresses lung cancer growth via increased NK cell and macrophage recruitment

Hintergrund: Lung cancer is nowadays the main cause of death among all cancers. CD26/DPP4 (dipeptidyl peptidase 4) is a transmembrane glycoprotein, that is constitutively expressed on hematopoetic cells, but also found on lung epithelial and endothelial cells. Previously, we found that the activity of CD26/DPP4 of lung cancer patients is four times higher than normal tissue. Here, we tested if CD26/DPP4-inhibition regulates lung cancer growth in mice.

Material und Methode: An orthotopic tumor model was employed by sc. injections of the mouse lung cancer (Lewis Lung Carcinoma (LLC)) and a human lung adenocarcinoma cell line (H460). These tumors were developed on mice (C57BL6 (n = 18): CD1-nude (n = 20)). The CD26/DPP4-inhibitor Vildagliptin was given in drinking water of 50 mg/kg daily dose. Tumor growth was evaluated by wet weight of tumor mass at 4 weeks. Histological assessments included TUNEL, immunohistochemistry (IHC) of F4/80 and NKp46. Gene analysis involving tumor immunity included IL-10, Arginase, IL-12, NKp46, NK1.1, IFN-g, Granzyme, and Perforin 1 were analyzed by RT-PCR. In vitro analysis of SP expression in LLC and H460 were performed by western blotting.

Ergebnis: Vildagliptin treatment significantly reduced the tumor growth of both, LLC and H460 in mice. IHC showed macrophages (F4/80) and NK cells (NKp46) to be significantly elevated by Vildagliptin, while TUNEL stain showed no difference. The anti-inflammatory markers (IL-10, and Arginase) were unchanged, while the pro-inflammatory cytokine IL-12 was significantly elevated. The NK cell markers NKp46, NK1.1, IFN-g, Granzyme and Perforin 1 were also significantly upregulated by Vildagliptin. Furthermore, we found enhanced SP expression in lung cancer cell lines by Vildagliptin treatment.

Schlussfolgerung: The Inhibition of CD26/DPP4 decreased lung cancer growth in models of mouse and human lung cancer cell lines and increased inflammatory macrophages and NK cells within the tumors. The increased expression of SP by Vildagliptin treatment in lung cancer cell lines suggests that surfactant production in lung cancer might activate macrophages to fight against lung cancer via recruitment of NK cells.