Immunosuppressive CD14+HLA-DRlow/- monocytes in prostate cancer.
OBJECTIVE
To determine if the levels of circulating myeloid-derived suppressor cells increase with progression of prostate cancer (PCa); to determine if such cells could contribute to the relative inefficiency of PCa immunotherapy.


METHODS
We analyzed peripheral blood mononuclear cells isolated from untreated PCa patients (uPCa; N = 18; mean age +/- SD: 72.1 +/- 6.9 years), tPCa (N = 22; 72.8 +/- 9.8 years) and age matched controls (AMC; N = 12; 68.8 +/- 7.5 years). We quantified surface marker phenotype, differentiation potential, effects on T cell proliferation and intracellular cytokines.


RESULTS
We observed an unexpectedly high percentage of a type of myeloid-derived suppressor cells, CD14(+)HLA-DR(low/-) monocytes, in tPCa (30.7 +/- 15.0% of CD14(+) cells) relative to AMC (4.1 +/- 6.5%, P < 0.0001) and uPCa (10.6 +/- 14.3%, P = 0.0001). The levels of CD14(+) HLA-DR(low/-) cells were significantly correlated with circulating PSA levels and treatment with LHRH-agonist leuprolide in combination with either an antiandrogen or dexamethasone. Monocytes from tPCa inhibited autologous T cell proliferation statistically significantly more effectively than AMC monocytes and were defective in their ability to differentiate into phenotypically mature dendritic cells. Isolated CD14(+)HLA-DR(low/-) cells expressed higher levels of intracellular interleukin-10 and suppressed T cell proliferation more effectively than isolated CD14(+)HLA-DR(+) cells.


CONCLUSIONS
This is the first report of CD14(+) cells exhibiting reduced expression of HLA-DR molecules in PCa patients. These cells suppress immune cell function in vitro and, plausibly, in vivo, a finding that must be factored into the design of immunotherapy protocols for PCa patients.
Vuk-Pavlović
Stanimir
S
Stem Cell Laboratory, Mayo Clinic Cancer Center, College of Medicine, Mayo Clinic, Rochester, Minnesota 55905, USA. vuk@mayo.edu
Bulur
Peggy A
PA
Lin
Yi
Y
Qin
Rui
R
Szumlanski
Carol L
CL
Zhao
Xinghua
X
Dietz
Allan B
AB
D020533:Angiogenesis Inhibitors / Q000627:therapeutic use; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use; D049109:Cell Proliferation; D003713:Dendritic Cells / Q000187:drug effects; D003907:Dexamethasone / Q000627:therapeutic use; D018450:Disease Progression; D004359:Drug Therapy, Combination; D006684:HLA-DR Antigens / Q000378:metabolism*; D006801:Humans; D007165:Immunosuppression Therapy; D016729:Leuprolide / Q000627:therapeutic use; D018950:Lipopolysaccharide Receptors / Q000378:metabolism*; D008297:Male; D009000:Monocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D017430:Prostate-Specific Antigen / Q000097:blood; D011471:Prostatic Neoplasms / Q000097:blood / Q000188:drug therapy / Q000276:immunology*; D013601:T-Lymphocytes / Q000187:drug effects
D020533:Angiogenesis Inhibitors; D018931:Antineoplastic Agents, Hormonal; D006684:HLA-DR Antigens; D018950:Lipopolysaccharide Receptors; D003907:Dexamethasone; D017430:Prostate-Specific Antigen; D016729:Leuprolide