Pancreatic adenocarcinoma induces bone marrow mobilization of myeloid-derived suppressor cells which promote primary tumor growth

Matthew R. Porembka, Jonathan B. Mitchem, Brian A. Belt, Chyi Song Hsieh, Hyang Mi Lee, John Herndon, William E. Gillanders, David C. Linehan, Peter Goedegebuure

Research output: Contribution to journalArticle

127 Scopus citations

Abstract

Purpose: Myeloid-derived suppressor cells (MDSC) are a heterogeneous population of immunosuppressive cells that are upregulated in cancer. Little is known about the prevalence and importance of MDSC in pancreas adenocarcinoma (PA). Experimental design: Peripheral blood, bone marrow, and tumor samples were collected from pancreatic cancer patients, analyzed for MDSC (CD15 +CD11b+) by Xow cytometry and compared to cancer-free controls. The suppressive capacity of MDSC (CD11b+Gr-1+) and the eVectiveness of MDSC depletion were assessed in C57BL/6 mice inoculated with Pan02, a murine PA, and treated with placebo or zoledronic acid, a potent aminobisphosphonate previously shown to target MDSC. The tumor microenvironment was analyzed for MDSC (Gr1+CD11b+), eVector T cells, and tumor cytokine levels. Results: Patients with PA demonstrated increased frequency of MDSC in the bone marrow and peripheral circulation which correlated with disease stage. Normal pancreas tissue showed no MDSC inWltrate, while human tumors avidly recruited MDSC. Murine tumors similarly recruited MDSC that suppressed CD8+ T cells in vitro and accelerated tumor growth in vivo. Treatment with zoledronic acid impaired intratumoral MDSC accumulation resulting in delayed tumor growth rate, prolonged median survival, and increased recruitment of T cells to the tumor. This was associated with a more robust type 1 response with increased levels of IFN-γ and decreased levels of IL-10. Conclusions: MDSC are important mediators of tumorinduced immunosuppression in pancreatic cancer. Inhibiting MDSC accumulation with zoledronic acid improves the host anti-tumor response in animal studies suggesting that eVorts to block MDSC may represent a novel treatment strategy for pancreatic cancer.

Original languageEnglish (US)
Pages (from-to)1373-1385
Number of pages13
JournalCancer Immunology, Immunotherapy
Volume61
Issue number9
DOIs
StatePublished - Sep 1 2012

Keywords

  • Myeloid-derived suppressor cells
  • Pancreatic cancer
  • Zoledronic acid

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Oncology
  • Cancer Research

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    Porembka, M. R., Mitchem, J. B., Belt, B. A., Hsieh, C. S., Lee, H. M., Herndon, J., Gillanders, W. E., Linehan, D. C., & Goedegebuure, P. (2012). Pancreatic adenocarcinoma induces bone marrow mobilization of myeloid-derived suppressor cells which promote primary tumor growth. Cancer Immunology, Immunotherapy, 61(9), 1373-1385. https://doi.org/10.1007/s00262-011-1178-0