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.
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Acknowledgments
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.
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Poschke, I., Mao, Y., Adamson, L. et al. Myeloid-derived suppressor cells impair the quality of dendritic cell vaccines. Cancer Immunol Immunother 61, 827–838 (2012). https://doi.org/10.1007/s00262-011-1143-y
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DOI: https://doi.org/10.1007/s00262-011-1143-y