CD26 as a potential therapeutic target for lung adenocarcinoma

Wolfgang Jungraithmayr^1*Birte Ohm¹Martina Haberecker²Alessandra Curioni-Fontecedro³Florian Janker⁴Ignacio Gil-Bazo⁵Alex Soltermann²Michaela B Kirschner²Walter Weder⁶Isabelle Opitz²Jae-Hwi Jang²

• ¹University of Freiburg Medical Center, Freiburg, Germany
• ²University Hospital Zürich, Zurich, Zürich, Switzerland
• ³Université de Fribourg, Fribourg, Fribourg, Switzerland
• ⁴University Hospital of Bern, Bern, Bern, Switzerland
• ⁵Department of Medical Oncology, Clinica Universidad de Navarra, Madrid, Asturias, Spain
• ⁶Private Clinic Bethanien, Zürich, Zürich, Switzerland

Introduction: CD26/dipeptidyl peptidase 4 (CD26, DPP4) is a transmembrane exopeptidase that modulates tumorigenesis in different malignancies. We demonstrated before that CD26 inhibition decreases lung tumor growth in experimental models. Here, we analysed the prognostic significance of CD26 expression and its correlation with epithelial-to-mesenchymal transition (EMT) markers in a large series of patients with non-small cell lung cancer (NSCLC). Patients & Methods: NSCLCs samples from operated patients were analysed by immunohistochemistry (IHC) for the expression of CD26 and EMT markers. CD26 was scored semiquantitatively employing tissue microarrays. Lung cancer cell lines (H460, LLC) were tested for EMT markers and a colony forming assay was used to test the effect of treatment with the CD26 inhibitor Vildagliptin. Results: Tumor samples from 904 patients with NSCLC were analysed. CD26 IHC expression was significantly higher in adenocarcinoma compared to squamous-cell carcinoma (p <0.0001). Patients with adenocarcinoma and CD26 expression had a better overall survival than patients without CD26 expression. The lack of CD26 expression was shown to be an independent risk factor for a worse survival. CD26 expressing adenocarcinomas showed a higher expression of Vimentin and Elastin (p=0.0027 and <0.0001, respectively) while E-cadherin expression was lower in this group of patients (p=0.0021). In vitro, treatment with Vildagliptin reduced the expression of Vimentin and the capacity for colony forming in H460 and LLC cell lines. Summary & Conclusion: The correlation of CD26 expression in lung adenocarcinomas and a better patient survival, the antiproliferative property on tumor cells by CD26 inhibition and an altered EMT status gives rise to the hypotheses that CD26 inhibitors impact the biology and clinical course of lung adenocarcinomas.