A listeria vaccine and depletion of t-regulatory cells activate immunity against early stage pancreatic intraepithelial neoplasms and prolong survival of mice

Bridget P. Keenan, Yvonne Saenger, Michel I. Kafrouni, Ashley Leubner, Peter Lauer, Anirban Maitra, Agnieszka A. Rucki, Andrew J. Gunderson, Lisa M. Coussens, Dirk G. Brockstedt, Thomas W. Dubensky, Raffit Hassan, Todd D. Armstrong, Elizabeth M. Jaffee

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Abstract

Background & Aims Premalignant lesions and early stage tumors contain immunosuppressive microenvironments that create barriers for cancer vaccines. KrasG12D/+;Trp53R172H/+;Pdx-1-Cre (KPC) mice, which express an activated form of Kras in pancreatic tissues, develop pancreatic intraepithelial neoplasms (PanIN) that progress to pancreatic ductal adenocarcinoma (PDA). We used these mice to study immune suppression in PDA. Methods We immunized KPC and KrasG12D/+;Pdx-1-Cre mice with attenuated intracellular Listeria monocytogenes (which induces CD4+ and CD8+ T-cell immunity) engineered to express KrasG12D (LM-Kras). The vaccine was given alone or in sequence with an anti-CD25 antibody (PC61) and cyclophosphamide to deplete T-regulatory (Treg) cells. Survival times were measured; pancreatic and spleen tissues were collected and analyzed by histologic, flow cytometry, and immunohistochemical analyses. Results Interferon γ-mediated, CD8+ T-cell responses were observed in KPC and KrasG12D/+;Pdx-1-Cre mice given LM-Kras, but not in unvaccinated mice. Administration of LM-Kras to KPC mice 4-6 weeks old (with early stage PanINs), depleted of Treg cells, significantly prolonged survival and reduced PanIN progression (median survival, 265 days), compared with unvaccinated mice (median survival, 150 days; P =.002), mice given only LM-Kras (median survival, 150 days; P =.050), and unvaccinated mice depleted of Treg cells (median survival, 170 days; P =.048). In 8- to 12-week-old mice (with late-stage PanINs), LM-Kras, alone or in combination with Treg cell depletion, did not increase survival time or slow PanIN progression. The combination of LM-Kras and Treg cell depletion reduced numbers of Foxp3+CD4 + T cells in pancreatic lymph nodes, increased numbers of CD4 + T cells that secrete interleukin 17 and interferon γ, and caused CD11b+Gr1+ cells in the pancreas to acquire an immunostimulatory phenotype. Conclusions Immunization of KPC mice with Listeria monocytogenes engineered to express KrasG12D, along with depletion of Treg cells, reduces progression of early stage, but not late-stage, PanINs. This approach increases infiltration of the lesion with inflammatory cells. It might be possible to design immunotherapies against premalignant pancreatic lesions to slow or prevent progression to PDA.

Original languageEnglish (US)
Pages (from-to)1784-1794.e6
JournalGastroenterology
Volume146
Issue number7
DOIs
StatePublished - Jun 2014

Keywords

  • Immunity
  • Listeria Vaccine
  • Pancreatic Cancer
  • Tumor Microenvironment

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology

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    Keenan, B. P., Saenger, Y., Kafrouni, M. I., Leubner, A., Lauer, P., Maitra, A., Rucki, A. A., Gunderson, A. J., Coussens, L. M., Brockstedt, D. G., Dubensky, T. W., Hassan, R., Armstrong, T. D., & Jaffee, E. M. (2014). A listeria vaccine and depletion of t-regulatory cells activate immunity against early stage pancreatic intraepithelial neoplasms and prolong survival of mice. Gastroenterology, 146(7), 1784-1794.e6. https://doi.org/10.1053/j.gastro.2014.02.055