Functional characterization of human Cd33 + And Cd11b + myeloid-derived suppressor cell subsets induced from peripheral
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RESEARCH
Open Access
Functional characterization of human Cd33+ And Cd11b+ myeloid-derived suppressor cell subsets induced from peripheral blood mononuclear cells co-cultured with a diverse set of human tumor cell lines Melissa G Lechner, Carolina Megiel, Sarah M Russell, Brigid Bingham, Nicholas Arger, Tammy Woo and Alan L Epstein*
Abstract Background: Tumor immune tolerance can derive from the recruitment of suppressor cell populations, including myeloid-derived suppressor cells (MDSC). In cancer patients, MDSC accumulation correlates with increased tumor burden, but the mechanisms of MDSC induction remain poorly understood. Methods: This study examined the ability of human tumor cell lines to induce MDSC from healthy donor PBMC using in vitro co-culture methods. These human MDSC were then characterized for morphology, phenotype, gene expression, and function. Results: Of over 100 tumor cell lines examined, 45 generated canonical CD33+HLA-DRlowLineage- MDSC, with high frequency of induction by cervical, ovarian, colorectal, renal cell, and head and neck carcinoma cell lines. CD33+ MDSC could be induced by cancer cell lines from all tumor types with the notable exception of those derived from breast cancer (0/9, regardless of hormone and HER2 status). Upon further examination, these and others with infrequent CD33+ MDSC generation were found to induce a second subset characterized as CD11b + CD33lowHLA-DRlowLineage-. Gene and protein expression, antibody neutralization, and cytokine-induction studies determined that the induction of CD33+ MDSC depended upon over-expression of IL-1b, IL-6, TNFa, VEGF, and GM-CSF, while CD11b+ MDSC induction correlated with over-expression of FLT3L and TGFb. Morphologically, both CD33+ and CD11b+ MDSC subsets appeared as immature myeloid cells and had significantly up-regulated expression of iNOS, NADPH oxidase, and arginase-1 genes. Furthermore, increased expression of transcription factors HIF1a, STAT3, and C/EBPb distinguished MDSC from normal counterparts. Conclusions: These studies demonstrate the universal nature of MDSC induction by human solid tumors and characterize two distinct MDSC subsets: CD33+HLA-DRlowHIF1a+/STAT3+ and CD11b+HLA-DRlowC/EBPb+, which should enable the development of novel diagnostic and therapeutic reagents for cancer immunotherapy. Keywords: myeloid-derived suppressor cells, tumor immune tolerance, human tumor cell lines, immunomodulation, cytokines, hypoxia-inducible factor 1 alpha, CAAAT-enhancer binding protein, signal transducer and activator of transcription, inflammation
* Correspondence: [email protected] Department of Pathology, USC Keck School of Medicine, Los Angeles, California, USA © 2011 Lechner et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Lechner et al. Journal of Translation
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