Abstract
BackgroundTumor 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.MethodsThis 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.ResultsOf 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-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.ConclusionsThese studies demonstrate the universal nature of MDSC induction by human solid tumors and characterize two distinct MDSC subsets: CD33+HLA-DRlowHIF1α+/STAT3+ and CD11b+HLA-DRlowC/EBPβ+, which should enable the development of novel diagnostic and therapeutic reagents for cancer immunotherapy.
Highlights
Tumor immune tolerance can derive from the recruitment of suppressor cell populations, including myeloid-derived suppressor cells (MDSC)
Unfractionated peripheral blood mononuclear cells (PBMC) preparations were used in evaluating the ability of human solid tumor cell lines to generate myeloid suppressor cells to best approximate an in vivo setting, but CD33+ suppressor cells were generated successfully from T celldepleted PBMC by co-culture with 4-998 osteogenic sarcoma or SCCL-MT1 head and neck squamous cell carcinoma (HNSCC) cells (Table 1)
We examined the expression of HIF1a, STAT3, and C/EBPb in tumor cell line (SCCLMT1 or USC-HN2)-induced CD33+ or (MCF7 breast or NCI-H60 small cell lung carcinoma) CD11b+ human suppressor cells compared with medium only controls by qRT-PCR techniques (Figure 8A) and immunohistochemistry (Figure 8B)
Summary
Tumor immune tolerance can derive from the recruitment of suppressor cell populations, including myeloid-derived suppressor cells (MDSC). Myeloid-derived suppressor cells (MDSC) have recently been recognized as a subset of innate immune cells that can alter adaptive immunity and produce immunosuppression [1]. MDSC inhibit T cell effector functions through a range of mechanisms, including: arginase 1 (ARG-1)-mediated depletion of L-arginine [7], inducible nitric oxide synthase (iNOS) and NADPH oxidase (NOX2) production of reactive nitrogen and oxygen species [8,9], vascular endothelial growth factor (VEGF) over-expression [10], cysteine depletion [11], and the expansion of T-regulatory (Treg) cell populations [12,13]. In cancer patients and experimental tumor models, MDSC are major contributors to tumor immune tolerance and the failure of anti-tumor immunity [1]. Preclinical models of human tumor-induced MDSC will significantly advance knowledge of their induction and function as suppressor cells
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
