title: Myeloid-derived suppressor cells impair the quality of dendritic cell vaccines.
abstract: Myeloid-derived suppressor cells (MDSC) are important regulators of the immune system and key players in tumor-induced suppression of T-cell responses. CD14+HLA-DR-/low MDSC have been detected in a great number of malignancies, including melanoma. MDSC are known to be impaired in their ability to differentiate along the myeloid lineage, e.g., into dendritic cells (DC). This is a concern for utilization of monocyte-derived DC for vaccination of patients with melanoma or other cancers exhibiting accumulation of CD14+ MDSC. When producing DC according to standard operating procedures of two currently ongoing clinical trials, we found that MDSC co-purified with monocytes isolated by elutriation. MDSC frequencies did not affect yield or viability of the produced DC, but induced a dose-dependent decrease in DC maturation, ability to take up antigen, migrate and induce T-cell IFNγ production. Changes in DC characteristics were most notable when 'pathological' frequencies of >50% CD14+HLA-DR- cells were present in the starting culture. The impaired DC quality could not be explained by altered cytokine production or increased oxidative stress in the cultures. Tracking of HLA-DR- cells throughout the culture period revealed that the observed changes were partially due to the impaired maturation and functionality of the originally HLA-DR- population, but also to their negative effects on HLA-DR+ cells. In conclusion, MDSC could be induced to differentiate into DC but, due to the impairment of overall DC vaccine quality when >50% HLA-DR- cells were present in the starting culture, their removal could be advisable.
authors.affiliation: Department of Oncology and Pathology, Cancer Center Karolinska, Karolinska Institutet, Stockholm, Sweden. Isabel.Poschke@ki.se
authors.forename: I
authors.initials: I
authors.lastname: Poschke
authors.forename: Y
authors.initials: Y
authors.lastname: Mao
authors.forename: L
authors.initials: L
authors.lastname: Adamson
authors.forename: F
authors.initials: F
authors.lastname: Salazar-Onfray
authors.forename: G
authors.initials: G
authors.lastname: Masucci
authors.forename: R
authors.initials: R
authors.lastname: Kiessling
mesh_terms: D000328:Adult; D000368:Aged; D019496:Cancer Vaccines / Q000276:immunology*; D018920:Coculture Techniques; D016207:Cytokines / Q000096:biosynthesis; D003713:Dendritic Cells / Q000276:immunology*; D005260:Female; D006684:HLA-DR Antigens / Q000276:immunology; D006801:Humans; D018950:Lipopolysaccharide Receptors / Q000276:immunology; D008297:Male; D008545:Melanoma / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D008875:Middle Aged; D022423:Myeloid Cells / Q000276:immunology*; D009367:Neoplasm Staging; D018384:Oxidative Stress / Q000276:immunology
chemical_list: D019496:Cancer Vaccines; D016207:Cytokines; D006684:HLA-DR Antigens; D018950:Lipopolysaccharide Receptors
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