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Patients with pancreatic adenocarcinoma exhibit elevated levels of myeloid-derived suppressor cells upon progression of disease

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Abstract

Elevated levels of myeloid-derived suppressor cells (MDSCs) induced by tumor-derived factors are associated with inhibition of immune responses in patients with gastrointestinal malignancies. We hypothesized that pro-MDSC cytokines and levels of MDSC in the peripheral blood would be elevated in pancreatic adenocarcinoma patients with progressive disease. Peripheral blood mononuclear cells (PBMCs) were isolated from 16 pancreatic cancer patients undergoing chemotherapy and phenotyped for MDSC using a five antigen panel (CD33, HLA-DR, CD11b, CD14, CD15). Patients with stable disease had significantly lower MDSC levels in the peripheral blood than those with progressive disease (1.41 ± 1.12 vs. 5.14 ± 4.58 %, p = 0.013, Wilcoxon test). A cutoff of 2.5 % MDSC identified patients with progressive disease. Patients with ECOG performance status ≥2 had a weaker association with increased levels of MDSC. Plasma was obtained from 15 chemonaive patients, 13 patients undergoing chemotherapy and 9 normal donors. Increases in the levels of pro-MDSC cytokines were observed for pancreatic cancer patients versus controls, and the pro-MDSC cytokine IL-6 was increased in those patients undergoing chemotherapy. This study suggests that MDSC in peripheral blood may be a predictive biomarker of chemotherapy failure in pancreatic cancer patients.

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Abbreviations

CCL5:

Chemokine (C-C motif) ligand 5 [synonym: RANTES]

CD:

Cluster of differentiation

CT:

Computerized tomography

FGF2:

Basic fibroblast growth factor

FOLFIRINOX:

Chemotherapy consisting of 5-FU, leucovorin, irinotecan and oxaliplatin

G-CSF:

Granulocyte colony-stimulating factor

HLA:

Human leukocyte antigen

IPA:

Ingenuity pathway analysis

MCP-1:

Monocyte chemotactic protein 1

MDSC:

Myeloid-derived suppressor cell

MIP-1α:

Macrophage inflammatory protein-1alpha

MPACT:

Metastatic pancreatic adenocarcinoma clinical trial

PBMC:

Peripheral blood mononuclear cell

PDGF-bb:

Platelet-derived growth factor–beta

RAGE:

Receptor for advanced glycation endproducts

RANTES:

Regulated on activation, normal T cell expressed and secreted [synonym: CCL5]

STAT3/SOC3:

Signal transducer and activator of transcription 3/suppressor of cytokine signaling 3

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Acknowledgments

We would like to acknowledge National Institute of Health grant T32CA090223 (William Edgar Carson, III) and the Pelotonia Postdoctoral Fellowship (to J. Markowitz). Taylor Brooks was supported by the Pelotonia undergraduate fellowship program. Any opinions, findings and conclusions expressed in this material are those of the author(s) and do not necessarily reflect those of the Pelotonia Fellowship Program. We would also like to acknowledge the National Cancer Institute grant P01CA095426.

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Division of Medical Oncology, The Ohio State University, Columbus, OH, USA

    Joseph Markowitz, Gregory B. Lesinski & Tanios Bekaii-Saab

  2. Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA

    Joseph Markowitz, Taylor R. Brooks, Megan C. Duggan, Bonnie K. Paul, Xueliang Pan, Lai Wei, Zachary Abrams, Gregory B. Lesinski, Bethany Mundy-Bosse, Tanios Bekaii-Saab & William E. Carson III

  3. Center for Biostatistics, The Ohio State University, Columbus, OH, USA

    Xueliang Pan & Lai Wei

  4. Biomedical Sciences Graduate Program, The Ohio State University, Columbus, OH, USA

    Megan C. Duggan

  5. Division of Surgical Oncology, The Ohio State University, N924 Doan Hall, 410 W. 10th Avenue, Columbus, OH, 43210, USA

    Eric Luedke & William E. Carson III

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  1. Joseph Markowitz
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Correspondence to William E. Carson III.

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Markowitz, J., Brooks, T.R., Duggan, M.C. et al. Patients with pancreatic adenocarcinoma exhibit elevated levels of myeloid-derived suppressor cells upon progression of disease. Cancer Immunol Immunother 64, 149–159 (2015). https://doi.org/10.1007/s00262-014-1618-8

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