Reversal of myeloid cell-mediated immunosuppression in patients with metastatic renal cell carcinoma.
Clinical cancer research : an official journal of the American Association for Cancer Research
Publication Date / Copyright Date
American Association for Cancer Research
PURPOSE: Tumor-induced immunosuppression remains a significant obstacle that limits the efficacy of biological therapy for renal cell carcinoma. Here we evaluate the role of CD33 myeloid-derived suppressor cells (MDSC) in the regulation of T-cell responses in renal cell carcinoma patients. We also examine effect of all-trans-retinoic acid (ATRA) on MDSC-mediated immune suppression.
EXPERIMENTAL DESIGN: CD33-positive myeloid cells were isolated from the peripheral blood of renal cell carcinoma patients with magnetic beads and tested in vitro for their ability to inhibit T-cell responses. T-cell function was evaluated using ELISPOT and CTL assays.
RESULTS: MDSC isolated from renal cell carcinoma patients, but not from healthy donors, were capable of suppressing antigen-specific T-cell responses in vitro through the secretion of reactive oxygen species and nitric oxide upon interaction with CTL. MDSC-mediated immune suppression and IFN-gamma down-regulation was reversible in vitro by exposing cells to the reactive oxygen species inhibitors. Moreover, ATRA was capable of abrogating MDSC-mediated immunosuppression and improving T-cell function by direct differentiation into antigen-presenting cell precursors.
CONCLUSIONS: These results may have significant implications regarding the future design of active immunotherapy protocols that may include differentiation agents as part of a multimodal approach to renal cell carcinoma immunotherapy.
Medicine and Health Sciences
Antigens, CD, Antigens, Differentiation, Myelomonocytic, Carcinoma, Renal Cell, Granulocyte-Macrophage Colony-Stimulating Factor, HLA-DR Antigens, Humans, Immune Tolerance, Kidney Neoplasms, Myeloid Cells, Sialic Acid Binding Ig-like Lectin 3, Tretinoin
Kusmartsev, Sergei; Su, Zhen; Heiser, Axel; Dannull, Jens; Eruslanov, Evgeniy; Kübler, Hubert; Yancey, Donna; Dahm, Philip; and Vieweg, Johannes, "Reversal of myeloid cell-mediated immunosuppression in patients with metastatic renal cell carcinoma." (2008). NSU-MD Faculty Articles. 48.