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F. Janker



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    MA04 - HER2, P53, KRAS and Other Targets in Advanced NSCLC (ID 380)

    • Event: WCLC 2016
    • Type: Mini Oral Session
    • Track: Advanced NSCLC
    • Presentations: 1
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      MA04.10 - Lung Cancer Growth is Suppressed by CD26/DPP4-Inhibition via Enhanced NK Cell and Macrophage Recruitment (ID 6143)

      16:00 - 17:30  |  Author(s): F. Janker

      • Abstract
      • Presentation
      • Slides

      Background:
      Lung cancer is the leading cause of death among cancers. There is broad evidence that immune cells are involved in the growth and development of these malignancies. CD26/DPP4 (dipeptidyl peptidase 4) is a transmembrane glycoprotein, that is constitutively expressed on hematopoetic cells, but also found on lung epithelial and endothelial cells. We found previously that the activity of CD26/DPP4 of lung cancer patients at early stages is four times higher than in normal tissue. Here, we tested if CD26/DPP4-inhibition is able to modulate lung cancer growth in mice.

      Methods:
      An orthotopic lung tumor model was employed by sc. injections of the mouse lung cancer (Lewis Lung Carcinoma (LLC)) and a human lung adenocarcinoma cell line (H460). These were developed in mice C57BL6 (n=18) and CD1-nude mice (n=20) respectively. The CD26/DPP4-inhibitor Vildagliptin was given in drinking water of 50mg/kg daily dose. Tumor growth was evaluated by wet weight of tumor mass at 2 weeks. Histological assessments included TUNEL, immunohistochemistry (IHC) of CD3, B220, F4/80 and NKp46. IL-10, Arginase, IL-12, NKp46, NK1.1, IFN-g, Granzyme, and Perforin 1 were analyzed by RT-PCR. In vitro analysis of surfactant protein (SP) expression in LLC and H460 were performed by western blotting. For a proof of concept, macrophage ablation was performed by clodronate-liposome during Vildagliptin treatment.

      Results:
      Vildagliptin treatment significantly reduced the tumor growth of both, LLC and H460 in mice. IHC showed macrophages (F4/80+) and NK cells (NKp46+) to be significantly increased by Vildagliptin within tumors, while TUNEL stain and IHC of T- and B cell infiltration did not show any difference. Gene expression levels of anti-inflammatory markers (IL-10, and Arginase) were unchanged, while the pro-inflammatory cytokine IL-12 was significantly elevated. The NK cell markers NKp46, NK1.1, IFN-g, Granzyme and Perforin 1 were significantly upregulated within the tumor by Vildagliptin, indicating that inhibition of CD26/DPP4 recruits NK cells into the tumor. Furthermore, we found enhanced SP expressions in lung cancer cell lines by Vildagliptin treatment in vitro. Macrophage ablation with clodronate-liposome in Vildagliptin treated mice reversed the tumor size significantly.

      Conclusion:
      The Inhibition of CD26/DPP4 decreased lung cancer growth in primary models of mouse and human lung cancer and increased inflammatory macrophages and NK cell cytotoxicity within those tumors. Furthermore, an increased expression of SP by Vildagliptin treatment in lung cancer cell lines suggests that surfactant production in lung cancer activates macrophages to fight against lung cancer via the recruitment of macrophages and NK cells.

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    P3.01 - Poster Session with Presenters Present (ID 469)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Biology/Pathology
    • Presentations: 1
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      P3.01-053 - Mouse Models of Primary Lung Cancer - A Thorough Evaluation (ID 6176)

      14:30 - 15:45  |  Author(s): F. Janker

      • Abstract

      Background:
      Lung cancer is the most prominent cancer in human with the highest mortality rate among cancer patients in both genders nowadays. Several models of primary lung cancer research are in use, however, no systematic evaluation of optimal models is available. Here, we assess and reappraise the most robust models of primary lung cancer for their suitability of cancer evolution and targetability for new therapeutics.

      Methods:
      Three models of primary lung cancer were evaluated: (I) Carcinogen (urethane or diethylnitrosamine (DEN)) induced lung cancer model, established via three intraperitoneal (i.p.) injections to BALB/c and C57BL/6 mouse strains. Five and ten months after injections, mice were assessed for tumor incidence. Lewis Lung Carcinoma (LLC) cell line was employed for an orthotopic development of lung tumor in syngeneic mouse. The cell line was injected (II) intravenously (i.v.) or (III) subcutaneously (s.c.) to establish lung tumor models in 14 days. Tumor nodules and tumor necrosis were confirmed by microscopy. Immunohistochemistry (IHC) of markers of proliferation (p-Histone3, inhibitor of differentiation 1 (Id1), and Ki67), immune cells (CD4, CD8, B220, F4/80, and NKp46), vascular structure (CD31), stroma (alpha-actin) were performed for a finer characterization of the tumor.

      Results:
      Ten months after i.p. injections of carcinogens, we found that the urethane model stably induced tumor nodules (90%: 9/10) when compared to DEN (30%: 3/10). BALB/c strain was significantly more susceptible for the urethane induced tumor development compared to C57BL/6 strain. Injection of LLC cell line via i.v. developed diffuse lung tumor without metastasis to other organs. s.c. injection also stably developed single tumor nodule (~500mg). IHC revealed that all tumors were consistently positive for the proliferation markers, and F4/80+ cells and CD4+ cells infiltrated into tumors significantly more than CD8+, B220+, or NKp46+ cells. Heterogeneous distributions of CD31+ cells and alpha-actin+ cells were observed in overall tumor models.

      Conclusion:
      The urethane-induced lung tumor is reliable and reproducible with a high rate of development and seems superior to DEN induced tumor, but need a long time period to develop. In contrast, the i.v. and s.c. tumor models are established within short time ranges. The tumors developed by s.c. enable for the analysis of the tumor only without adjacent tissue bias. The involvement and characteristics of immune cells found within tumors were comparable across all models. Injections by i.v. or s.c. of cell line to mouse can be considered as an alternative yet convenient model to develop various different types of lung cancers.