Reversal of myeloid cell-mediated immunosuppression in patients with metastatic renal cell carcinoma.
OBJECTIVE
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.


METHODS
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.
Kusmartsev
Sergei
S
Department of Urology, College of Medicine, University of Florida, Gainesville, Florida 32610-0247, USA.
Su
Zhen
Z
Heiser
Axel
A
Dannull
Jens
J
Eruslanov
Evgeniy
E
Kübler
Hubert
H
Yancey
Donna
D
Dahm
Philip
P
Vieweg
Johannes
J
D015703:Antigens, CD / Q000032:analysis; D015214:Antigens, Differentiation, Myelomonocytic / Q000032:analysis; D002292:Carcinoma, Renal Cell / Q000276:immunology*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006684:HLA-DR Antigens / Q000032:analysis; D006801:Humans; D007108:Immune Tolerance; D007680:Kidney Neoplasms / Q000276:immunology*; D022423:Myeloid Cells / Q000502:physiology*; D063268:Sialic Acid Binding Ig-like Lectin 3; D014212:Tretinoin / Q000494:pharmacology
D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; C571163:CD33 protein, human; D006684:HLA-DR Antigens; D063268:Sialic Acid Binding Ig-like Lectin 3; D014212:Tretinoin; D016178:Granulocyte-Macrophage Colony-Stimulating Factor