Hintergrund:
Previous experimental data from our group showed that the activity of CD26 is increased in lung cancer. We therefore hypothesized that the inhibition of CD26 can suppress lung cancer in animal models.
Material und Methode:
The CD26/DPP4 inhibitor Vildagliptin was applied as a treatment in tumor models which were developed by injection of the Lewis Lung Carcinoma (LLC) mouse cell line and human lung adenocarcinoma (H460) cell line.
Ergebnis:
Two weeks after subcutaneous injection of cell lines, we found the size of LLC and H460 tumors to be significantly reduced by Vildagliptin treatment (p < 0.01). Immunohistochemically, the number of macrophages (M) (F4/80+) and NK cells (NKp46+) was significantly increased in Vildagliptin-treated tumors (p < 0.01). Mechanistically, we found that tumors expressed increased levels of surfactant protein (p < 0.01) in vitro thereby promoting the pro-inflammatory activity of M (p < 0.001). Upon depletion of M by Clodronate and by using NK cell deficient (IL-15-/-) mice, the size of tumors reversed to the size of control and thereby abolished the observed tumor-suppressing effect induced by Vildagliptin treatment. FACS analysis showed tumor-associated NK cells to express TRAIL, which induces the intra-cellular stress marker γH2AX (p < 0.05). In line with these data, we found γH2AX to be upregulated in Vildagliptin-treated tumors in vivo, and in TRAIL-treated LLC cell lines in vitro (p < 0.05).
Schlussfolgerung:
These data provide evidence that the CD26/DPP4-inhibitor Vildagliptin suppresses lung cancer growth. This effect is exerted by surfactant-activated M and NK cells that act against the tumor via a TRAIL-mediated cytotoxicity.
