Myeloid-derived suppressor cells impair the quality of dendritic cell vaccines
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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.
KeywordsMDSC Dendritic cells Melanoma Vaccination Cancer
This study was supported by grants from the Swedish Cancer Society, the Swedish Medical Research Council, the Cancer Society of Stockholm, the European Union (Grants “EUCAAD” and “DC-THERA”), the Karolinska Institutet, an “ALF-Project” grant from the Stockholm City Council, the Robert Lundgrens Foundation, the Sigurd and Elsa Goljes Memorial foundation and Lars Hiertas Memorial Foundation.
Conflict of interest
The authors declare that they have no conflict of interest.
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