Published in Cancer Detection and Prevention 2000; 24(Supplement 1).

Pancreatic cell carcinoma-derived Vascular Endothelial Factor and Interleukin-10 differentially affect dendritic cells development

C Smirne MD, B Nuschak BS, C Rivetti MD, I Ferrero BS, R Segir BS, A Carbone BS, D Tibaudi MD, F Suman MD, G Emanuelli MD, G Bellone PhD

Dept Clinical Physiopathology, University of Torino, Torino, Italy,

AIM Dendritic cells (DC) are professional antigen-presenting cells required for the initiation of primary T-cell response in vivo. It has been suggested that malignant cells produce a variety of immunomodulatory cytokines affecting the host response to tumor. The escape of tumor cells from the immune response may result from a defective DC development or function. The present study was performed to explore the effects of two of such cytokines aberrantly produced by pancreatic tumor cells, Vascular Endothelial Growth Factor (VEGF) and Interleukin (IL)-10, on the differentiation of the two distinct types of DC precursors, pDC1 and pDC2. METHODS To generate DC1 in vitro, monocytes isolated by plastic adherence from blood mononuclear cells were cultured for 6 days with GM-CSF (100 ng/ml) and IL-4 (5 ng/ml), in the presence or absence of VEGF (100 ng/ml), IL-10 (10 ng/ml) and 20% supernatants from pancreatic carcinoma cell lines PT-45, BxPC-3 and Capan-2. DC2 were generated from blood CD4+CD3-CD11c- cells cultured with IL-3 (50 ng/ml) for 6 days, in the presence or absence of VEGF (200 ng/ml), IL-10 (10 ng/ml) and 20% supernatants from the pancreatic carcinoma cell lines. RESULTS Exogenous VEGF was found to inhibit preferentially the differentiation of DC2. By contrast, IL-10 prevented the generation of DC1. Conditioned media from the three pancreatic carcinoma cell lines affected both DC type generation. Pre-treatment of supernatants with neutralizing antibody against IL-10 preferentially restored DC1 differentiation, while neutralizing antibody against VEGF significantly restored DC2 generation. CONCLUSIONS Since lymphoid cell-derived DC2 are known to induce Th2 differentiation, whereas monocyte-derived DC1 induce Th1 differentiation, we can speculate that the tumor, by the combined release of VEGF and IL-10, may hamper the development of the two distinct subsets of CD4+ cells, both required in generating an effective anti-tumor immune response.

KEY WORDS: Dendritic cells, pancreatic carcinoma, T cell differentiation.

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Paper presented at the International Symposium on Impact of Biotechnology on Cancer Diagnostic & Prognostic Indicators; Geneva, Switzerland; October 28 - 31, 2000; in the section on immunotherapy.