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

• Main Authors: Arger Nicholas, Bingham Brigid, Russell Sarah M, Megiel Carolina, Lechner Melissa G, Woo Tammy, Epstein Alan L
• Format: Article
• Language: English
• Published: BMC 2011-06-01
• Series: Journal of Translational Medicine
• Subjects: 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
• Online Access: http://www.translational-medicine.com/content/9/1/90
• ISSN: 1479-5876

<p>Abstract</p> <p>Background</p> <p>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.</p> <p>Methods</p> <p>This study examined the ability of human tumor cell lines to induce MDSC from healthy donor PBMC using <it>in vitro </it>co-culture methods. These human MDSC were then characterized for morphology, phenotype, gene expression, and function.</p> <p>Results</p> <p>Of over 100 tumor cell lines examined, 45 generated canonical CD33⁺HLA-DR^lowLineage^-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⁺CD33^lowHLA-DR^lowLineage^-. Gene and protein expression, antibody neutralization, and cytokine-induction studies determined that the induction of CD33⁺MDSC depended upon over-expression of IL-1β, IL-6, TNFα, VEGF, and GM-CSF, while CD11b⁺MDSC induction correlated with over-expression of FLT3L and TGFβ. 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 HIF1α, STAT3, and C/EBPβ distinguished MDSC from normal counterparts.</p> <p>Conclusions</p> <p>These studies demonstrate the universal nature of MDSC induction by human solid tumors and characterize two distinct MDSC subsets: CD33⁺HLA-DR^lowHIF1α⁺/STAT3⁺and CD11b⁺HLA-DR^lowC/EBPβ⁺, which should enable the development of novel diagnostic and therapeutic reagents for cancer immunotherapy.</p>