Abstract B15: Immunochemotherapy with 5-fluorouracil and interferon-enhances innate and adoptive immune responses against pancreatic cancer in vivo

Abstract

Abstract Pancreatic cancer has the poorest prognosis of all cancers urging the necessity of new therapeutic approaches. Recent clinical data show encouraging results for combining Interferon-α (IFN-α) immunotherapy with 5-Fluorouacil (5-FU) chemotherapy. However, the role of IFN-α in this immunochemotherapy scheme is still elusive. Here we investigate in vivo the relevance of different immune subpopulations in the anti-cancer immune response mediated by IFN-α in combination with 5-FU. Luciferase-transfected Panc02 cells were implanted in the pancreas of C57BL/6 mice. Five days later, mice were treated with 5-FU alone, 5-FU + IFN-α or with a vehicle control. In parallel, CD4+ T cells, CD8+ T cells, and NK cells were depleted by neutralizing antibodies. Depletion of CD11c+ dendritic cells (DCs) was performed using transgenic CD11c.DTR mice. On day 21, tumor volume was measured and NK cells were isolated and enriched from spleens of mice then used as effectors against Panc02 cells in a standard chromium release assay. Tumors were frozen for further immunohistochemistry analysis to evaluate the immune cells infiltration. In parallel, we performed flow cytometry analysis to evaluate the effects of different treatments on the expression of MHC-I and NKG2D ligands (MULT-1 and Rae-1) on Panc02 cells. Our data show that treatment with IFN-α + 5-FU has significantly decreased tumor volume in comparison with control or 5-FU treatments. This decrease in tumor volume was remarkably abolished by depleting CD8+ T cells or NK cells. Furthermore, NK cells isolated from spleens of IFN-α + 5-FU treated mice showed enhanced cytotoxicity towards Panc02 cells. Moreover, IFN-α + 5-FU treatment enhances the expression of MHC-I and NKG2D-ligand MULT-1 on Panc02 cells which could be the possible key for the enhanced recognition and per se killing by CD8+ T cells and NK cells respectively. To conclude, this study gives more insight about the mechanism of action of INF-α in combination with 5-FU and introduces CD8+ T cells and NK cells as main players in the observed anti-cancer immune response. Citation Information: Clin Cancer Res 2010;16(7 Suppl):B15