Non-redundant role for IL-12 and IL-27 in modulating Th2 polarization of carcinoembryonic antigen specific CD4 T cells from pancreatic cancer patients

Elena Tassi, Marco Braga, Renato Longhi, Francesca Gavazzi, Giorgio Parmiani, Valerio Di Carlo, Maria Pia Protti

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Abstract

Background: Pancreatic cancer is a very aggressive disease with dismal prognosis; peculiar is the tumor microenvironment characterized by an extensive fibrotic stroma, which favors rapid tumor progression. We previously reported that pancreatic cancer patients have a selective Th2 skew in the anti-carcinoembryonic antigen (CEA) CD4+ T cell immunity, which correlates with the presence of a predominant GATA-3+ tumor lymphoid infiltrate. This has negative effects in both effective anti-tumor immunity and further favoring fibrinogenesis. Aim of this study was to evaluate whether the Th2 polarization of CEA-specific CD4+ T cells from pancreatic cancer patients is stable or can be reverted by immunomodulating cytokines. Methodology/Principal Findings: We first evaluated the influence of IL-12 and IL-27, as single agents and in association, on the polarization of CEA-specific Th2 CD4+ T cell clones from a pancreatic cancer patient. We found that only the combination of IL-12 and IL-27 modified the polarization of Th2 effectors by both reduction of IL-5, GM-CSF and IL-13 and induction of IFN-γ production, which lasted after cytokine removal. Second, we evaluated the effect of the combined treatment on polyclonal CEA-specific CD4+ T cells in short-time re-stimulation assays. In agreement with the data obtained with the clones, we found that the combined treatment functionally modulated the Th2 polarization of CEA-specific CD4+ T cells and enhanced pre-existing Th1 type immunity. Conclusions/Significance: Collectively, our results demonstrate that tumor antigen specific Th2 CD4+ T cells in pancreatic cancer are endowed with functional plasticity. Hence, loco-regional cytokines delivery or targeted therapy based on antibodies or molecules directed to the tumor stroma might improve anti-tumor immunity and ameliorate fibrosis, without systemic toxicity.

Original languageEnglish
Article numbere7234
JournalPLoS One
Volume4
Issue number10
DOIs
Publication statusPublished - Oct 2 2009

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ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

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