The CD26/DPP4-inhibitor vildagliptin suppresses lung cancer growth via macrophage-mediated NK cell activity. (29th January 2019)

• Record Type: Journal Article
• Authors: Jang, Jae-Hwi; Janker, Florian; De Meester, Ingrid; Arni, Stephan; Borgeaud, Nathalie; Yamada, Yoshito; Gil Bazo, Ignacio; Weder, Walter; Jungraithmayr, Wolfgang
• Is Part Of: Carcinogenesis. Volume 40:Number 2(2019)
• Page Start: 324
• Page End: 334
• Publication Date: 2019-01-29
• Subjects: Carcinogenesis -- Periodicals; Cancer -- Genetic aspects -- Periodicals; Cancer -- Prevention -- Periodicals; Cancer -- Periodicals; 616.994071
• DOI: 10.1093/carcin/bgz009
• Languages: English
• ISSNs: 0143-3334

Abstract

Abstract: CD26/dipeptidyl peptidase 4 (DPP4) is a transmembrane protein which is expressed by various malignant cells. We found that the expression of CD26/DPP4 was significantly higher in lung adenocarcinoma samples in our own patient cohort compared to normal lung tissue. We therefore hypothesize that the inhibition of CD26/DPP4 can potentially suppress lung cancer growth. The CD26/DPP4 inhibitor vildagliptin was employed on Lewis Lung Carcinoma (LLC) cell line and a human lung adenocarcinoma (H460) cell line. Two weeks after subcutaneous injection of tumor cells into C57BL/6 and CD1/nude mice, the size of LLC and H460 tumors was significantly reduced by vildagliptin. Immunohistochemically, the number of macrophages (F4/80 + ) and NK cells (NKp46 + ) was significantly increased in vildagliptin-treated tumor samples. Mechanistically, we found in vitro that lung cancer cell lines expressed increased levels of surfactant protein upon vildagliptin treatment thereby promoting the pro-inflammatory activity of macrophages. By the depletion of macrophages with clodronate and by using NK cell deficient (IL-15 -/- ) mice, tumors reversed to the size of controls, suggesting that indeed macrophages and NK cells were responsible for the observed tumor-suppressing effect upon vildagliptin treatment. FACS analysis showed tumor-infiltrating NK cells to express tumor necrosis-related apoptosis-inducing ligand (TRAIL) which induced the intra-cellular stress marker γH2AX. Accordingly, we found upregulated γH2AX in vildagliptin-treated tumors and TRAIL-treated cell lines. Moreover, the effect of vildagliptin-mediated enhanced NK cell cytotoxicity could be reversed by antagonizing the TRAIL receptor. Our data provide evidence that the CD26/DPP4-inhibitor vildagliptin reduces lung cancer growth. We could demonstrate that this effect is exerted by surfactant-activated macrophages and NK cells that act against the tumor via TRAIL-mediated cytotoxicity. Abstract : Accumulating evidence suggests that CD26/DPP4 expression plays a potential role in lung cancer. We here show that the CD26/DPP4-inhibitor vildagliptin reduces lung cancer growth via surfactant-activated Type I macrophages and TRAIL-mediated NK cell cytotoxicity.