Department of Thoracic Surgery, University Hospital Zurich, Zurich, Switzerland.
Department of Medical Biochemistry, University of Antwerp, Antwerp, Belgium.
Carcinogenesis. 2019 Apr 29;40(2):324-334. doi: 10.1093/carcin/bgz009.
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.
CD26/二肽基肽酶 4（DPP4）是一种跨膜蛋白，多种恶性细胞均表达该蛋白。我们发现，与正常肺组织相比，我们自己的患者队列中的肺腺癌样本中 CD26/DPP4 的表达显著更高。因此，我们假设抑制 CD26/DPP4 可能潜在抑制肺癌生长。采用 CD26/DPP4 抑制剂维达列汀作用于 Lewis 肺癌细胞（LLC）和人肺腺癌细胞（H460）系。肿瘤细胞皮下注射到 C57BL/6 和 CD1/裸鼠两周后，维达列汀显著缩小 LLC 和 H460 肿瘤的大小。免疫组化结果显示，维达列汀处理的肿瘤样本中巨噬细胞（F4/80+）和 NK 细胞（NKp46+）的数量显著增加。机制上，我们发现肺癌细胞系在维达列汀处理后表达增加的表面活性蛋白，从而促进巨噬细胞的促炎活性。用氯膦酸盐耗尽巨噬细胞，并使用 NK 细胞缺陷（IL-15-/-）小鼠，肿瘤恢复到对照的大小，表明确实巨噬细胞和 NK 细胞对维达列汀治疗观察到的肿瘤抑制作用负责。FACS 分析显示肿瘤浸润性 NK 细胞表达肿瘤坏死相关凋亡诱导配体（TRAIL），诱导细胞内应激标志物 γH2AX。因此，我们发现维达列汀处理的肿瘤和 TRAIL 处理的细胞系中 γH2AX 上调。此外，维达列汀介导的增强 NK 细胞细胞毒性的作用可以通过拮抗 TRAIL 受体而逆转。我们的数据提供了证据表明，CD26/DPP4 抑制剂维达列汀可减少肺癌生长。我们能够证明这种作用是由表面活性剂激活的巨噬细胞和 NK 细胞通过 TRAIL 介导的细胞毒性作用于肿瘤。
