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


METHODS
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.
Department of Surgery, Washington University School of Medicine, 660 S Euclid Avenue, Box 8109, Saint Louis, MO 63110, USA.
Matthew R
MR
Porembka
Jonathan B
JB
Mitchem
Brian A
BA
Belt
Chyi-Song
CS
Hsieh
Hyang-Mi
HM
Lee
John
J
Herndon
William E
WE
Gillanders
David C
DC
Linehan
Peter
P
Goedegebuure
D000230:Adenocarcinoma / Q000276:immunology / Q000473:pathology*; D000818:Animals; D001854:Bone Marrow Cells / Q000187:drug effects / Q000276:immunology / Q000473:pathology*; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D004164:Diphosphonates / Q000494:pharmacology; D004195:Disease Models, Animal; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D022423:Myeloid Cells / Q000187:drug effects / Q000276:immunology / Q000473:pathology*; D010190:Pancreatic Neoplasms / Q000276:immunology / Q000473:pathology*; D059016:Tumor Microenvironment; D015854:Up-Regulation; D000077211:Zoledronic Acid
D004164:Diphosphonates; D007093:Imidazoles; D000077211:Zoledronic Acid