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PANCREAS |
1 Department of Internal Medicine I, University of Bonn, 53105 Bonn, Germany
2 Department of Internal Medicine II, University of Bonn, 53105 Bonn, Germany
3 Department of Pathology, University of Bonn, 53105 Bonn, Germany
4 Department of Surgery, University of Heidelberg, 69120 Heidelberg, Germany
5 Wound Healing Research Group, BioTec-Gründerzentrum, 38124 Braunschweig, Germany
Correspondence to:
Correspondence to:
Dr A Märten
Im Neuenheimer Feld 350 Heidelberg, Germany; angela.maerten{at}med.uni-heidelberg,de
Background and aim: Carcinoma of the exocrine pancreas has a particularly poor prognosis. Therefore, novel therapeutic strategies such as immunotherapy are required. Here we investigated the immunomodulatory capacity of macrophage activating lipopeptide 2 (MALP-2), which binds to toll-like receptors 2 and 6 and induces activation of nuclear factor 
B in monocytes. This causes the release of early stage leucocyte attracting chemokines and proinflammatory cytokines.
Methods: MALP-2 was tested in a new orthotopic ultrasound guided pancreatic cancer mouse model. This model is close to the biological situation and avoids the stress and immunostimulation caused by laparotomy. Cells from the syngeneic, highly aggressive, and metastatic cell line Panc 02 were administered orthotopically, by ultrasound guidance, to C57bl/6 mice. MALP-2 was administered intratumorally or intraperitoneally and tumour growth, immune status, and leucocyte infiltration at the tumour site were determined.
Results: We showed a tumour suppressive effect induced by a single injection of MALP-2. Median survival increased from 21 to 30 days (p<0.002). Combining chemotherapy (gemcitabine) with MALP-2 treatment caused further prolonged survival (median survival 27 days with chemotherapy alone v 37 days for combined treatment; p<0.0002). The life prolonging effect was paralleled by a significant increase in cytotoxic T cells, restoration of ß2 integrin expression on lymphocytes, and high expression of CD45RB on T helper cells. Immunohistochemical stains showed strong cytotoxic T lymphocyte and natural killer cell infiltration.
Conclusions: In conclusion, in a model of orthotopic pancreatic cancer in mice, we induced a tumour suppressive effect by treatment with a synthetic lipopeptide. Treatment with MALP-2 could be an option for immunotherapy in pancreatic cancer.
Keywords: tumour suppression; macrophage activating lipopeptide; MALP-2; pancreatic carcinoma; mouse model; immunotherapy
Abbreviations: MALP-2, macrophage activating lipopeptide 2; NK, natural killer; iNOS, inducible nitric oxide synthase; TLR, toll-like receptor; IL, interleukin; TNF-
, tumour necrosis factor ; PBS, phosphate buffered saline
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