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Cancer Immunology, Immunotherapy

, Volume 61, Issue 9, pp 1373–1385 | Cite as

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
Original article

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 flow cytometry and compared to cancer-free controls. The suppressive capacity of MDSC (CD11b+Gr-1+) and the effectiveness 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+), effector 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 infiltrate, 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 tumor-induced immunosuppression in pancreatic cancer. Inhibiting MDSC accumulation with zoledronic acid improves the host anti-tumor response in animal studies suggesting that efforts to block MDSC may represent a novel treatment strategy for pancreatic cancer.

Keywords

Myeloid-derived suppressor cells Pancreatic cancer Zoledronic acid 

Notes

Acknowledgment

This study was supported by a grant from the National Institutes of Health (T32CA009621).

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Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  • Matthew R. Porembka
    • 1
  • Jonathan B. Mitchem
    • 1
  • Brian A. Belt
    • 1
  • Chyi-Song Hsieh
    • 2
  • Hyang-Mi Lee
    • 2
  • John Herndon
    • 1
  • William E. Gillanders
    • 1
    • 3
  • David C. Linehan
    • 1
    • 3
  • Peter Goedegebuure
    • 1
    • 3
  1. 1.Department of SurgeryWashington University School of MedicineSaint LouisUSA
  2. 2.Department of RheumatologyWashington University School of MedicineSaint LouisUSA
  3. 3.Alvin J. Siteman Cancer CenterWashington University School of MedicineSaint LouisUSA

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