Induction of Th17 cells in the tumor microenvironment improves survival in a murine model of pancreatic cancer

Jennifer L. Gnerlich, Jonathan B. Mitchem, Joshua S. Weir, Narendra V. Sankpal, Hiroyuki Kashiwagi, Brian A. Belt, Matthew R. Porembka, John M. Herndon, Timothy J. Eberlein, Peter Goedegebuure, David C. Linehan

Research output: Contribution to journalArticle

83 Scopus citations

Abstract

An important mechanism by which pancreatic cancer avoids antitumor immunity is by recruiting regulatory T cells (Tregs) to the tumor microenvironment. Recent studies suggest that suppressor Tregs and effector Th17 cells share a common lineage and differentiate based on the presence of certain cytokines in the microenvironment. Because IL-6 in the presence of TGF-β has been shown to inhibit Treg development and induce Th17 cells, we hypothesized that altering the tumor cytokine environment could induce Th17 and reverse tumor-associated immune suppression. Pan02 murine pancreatic tumor cells that secrete TGF-β were transduced with the gene encoding IL-6. C57BL/6 mice were injected s.c. with wild-type (WT), empty vector (EV), or IL-6-transduced Pan02 cells (IL-6 Pan02) to investigate the impact of IL-6 secretion in the tumor microenvironment. Mice bearing IL-6 Pan02 tumors demonstrated significant delay in tumor growth and better overall median survival compared with mice bearing WT or EV Pan02 tumors. Immunohistochemical analysis demonstrated an increase in Th17 cells (CD4+IL-23R+ cells and CD4+IL- 17+ cells) in tumors of the IL-6 Pan02 group compared with WT or EV Pan02 tumors. The upregulation of IL-17-secreting CD4+ tumorinfiltrating lymphocytes was substantiated at the cellular level by flow cytometry and ELISPOT assay and mRNA level for retinoic acid-related orphan receptor γt and IL-23R by RT-PCR. Thus, the addition of IL-6 to the tumor microenvironment skews the balance toward Th17 cells in a murine model of pancreatic cancer. The delayed tumor growth and improved survival suggests that induction of Th17 in the tumor microenvironment produces an antitumor effect.

Original languageEnglish (US)
Pages (from-to)4063-4071
Number of pages9
JournalJournal of Immunology
Volume185
Issue number7
DOIs
StatePublished - Oct 1 2010

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Gnerlich, J. L., Mitchem, J. B., Weir, J. S., Sankpal, N. V., Kashiwagi, H., Belt, B. A., Porembka, M. R., Herndon, J. M., Eberlein, T. J., Goedegebuure, P., & Linehan, D. C. (2010). Induction of Th17 cells in the tumor microenvironment improves survival in a murine model of pancreatic cancer. Journal of Immunology, 185(7), 4063-4071. https://doi.org/10.4049/jimmunol.0902609