Immunosuppressive CD14+HLA-DRlow/- monocytes in prostate cancer

Prostate. 2010 Mar 1;70(4):443-55. doi: 10.1002/pros.21078.

Abstract

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.

Materials and 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiogenesis Inhibitors / therapeutic use
  • Antineoplastic Agents, Hormonal / therapeutic use
  • Cell Proliferation
  • Dendritic Cells / drug effects
  • Dexamethasone / therapeutic use
  • Disease Progression
  • Drug Therapy, Combination
  • HLA-DR Antigens / metabolism*
  • Humans
  • Immunosuppression*
  • Leuprolide / therapeutic use
  • Lipopolysaccharide Receptors / metabolism*
  • Male
  • Monocytes / drug effects
  • Monocytes / immunology*
  • Monocytes / metabolism
  • Prostate-Specific Antigen / blood
  • Prostatic Neoplasms / blood
  • Prostatic Neoplasms / drug therapy
  • Prostatic Neoplasms / immunology*
  • T-Lymphocytes / drug effects

Substances

  • Angiogenesis Inhibitors
  • Antineoplastic Agents, Hormonal
  • HLA-DR Antigens
  • Lipopolysaccharide Receptors
  • Dexamethasone
  • Prostate-Specific Antigen
  • Leuprolide