The CD26/DPP4-inhibitor vildagliptin suppresses lung cancer growth via macrophage-mediated NK cell activity
The CD26/DPP4-inhibitor vildagliptin suppresses lung cancer growth via macrophage-mediated NK cell activity
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DOI：
10.1093/carcin/bgz009
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发表时间：
2019-02-01
期刊：
影响因子：
4.7
通讯作者：
Jungraithmayr, Wolfgang
中科院分区：
文献类型：
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作者：
Jang, Jae-Hwi;Janker, Florian;Jungraithmayr, Wolfgang
CD 26/二肽基肽酶4（DPP 4）是一种跨膜蛋白，由多种恶性细胞表达。我们发现，在我们自己的患者队列中，与正常肺组织相比，肺腺癌样本中CD 26/DPP 4的表达显著更高。因此，我们假设抑制CD 26/DPP 4可以潜在地抑制肺癌生长。在刘易斯肺癌（LLC）细胞系和人肺腺癌（H460）细胞系上使用CD 26/DPP 4抑制剂维达利。将肿瘤细胞皮下注射到C57 BL/6和CD 1/裸鼠中后两周，LLC和H460肿瘤的大小被vildaglavine显著减小。免疫组织化学显示，在维格列汀处理的肿瘤样品中，巨噬细胞（F4/80（+））和NK细胞（NKp 46（+））的数量显著增加。从机制上讲，我们在体外发现，肺癌细胞系在维格鲁肽治疗后表达增加的表面活性蛋白水平，从而促进巨噬细胞的促炎活性。通过用氯膦酸盐消耗巨噬细胞和使用NK细胞缺陷型（IL-15（-/-））小鼠，肿瘤逆转至对照组的大小，表明巨噬细胞和NK细胞确实负责观察到的维达鲁治疗后的肿瘤抑制作用。FACS分析显示肿瘤浸润NK细胞表达肿瘤坏死相关凋亡诱导配体（TRAIL），其诱导细胞内应激标志物γ H2 AX。因此，我们在维格列汀处理的肿瘤和TRAIL处理的细胞系中发现了上调的γ H2 AX。此外，通过拮抗TRAIL受体，可以逆转维格列汀介导的增强NK细胞的细胞毒作用。我们的数据提供了CD 26/DPP 4抑制剂vildagelatin降低肺癌生长的证据。我们可以证明这种作用是由表面活性剂活化的巨噬细胞和NK细胞通过TRAIL介导的细胞毒性作用于肿瘤。
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 gamma H2AX. Accordingly, we found upregulated gamma H2AX 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.