Oxidative stress regulates expression of VEGFR1 in myeloid cells: link to tumor-induced immune suppression in renal cell carcinoma.
Metastatic renal cell carcinoma (RCC) associates with overproduction of vascular endothelial growth factor (VEGF) due to the mutation/inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene. Herein we demonstrate that implantation of human RCC tumor cells into athymic nude mice promotes the appearance of VEGF receptor 1 (VEGFR1)/CD11b double-positive myeloid cells in peripheral blood. Avastin-mediated VEGF neutralization was capable of significantly reducing the numbers of circulating VEGFR1+ myeloid cells. Conversely, up-regulation of VEGFR1 by myeloid cells could also be achieved in vitro by coculturing bone marrow cells with RCC-conditioned medium or by short-term exposure of naive myeloid cells to oxidative stress. Treatment of myeloid cells with H2O2, lipid peroxidation product 4-hydroxy-2(E)-nonenal, or an inhibitor of thioredoxin reductase all resulted in increased expression of VEGFR1. Furthermore, after exposure to oxidative stress, myeloid cells acquire immunosuppressive features and become capable of inhibiting T cell proliferation. Data suggest that tumor-induced oxidative stress may promote both VEGFR1 up-regulation and immunosuppressive function in bone marrow-derived myeloid cells. Analysis of tumor tissue and peripheral blood from patients with metastatic RCC revealed that VEGFR1+ cells can be also found in cancer patients. Restoration of immunocompetence in metastatic RCC patients by pharmacological elimination of VEGFR1+ cells may have a significant impact on the therapeutic efficacy of cancer vaccines or other immune-based therapies.
Department of Urology, College of Medicine, University of Florida, Gainesville, FL 32610, USA. s.kusmartsev@urology.ufl.edu
Sergei
S
Kusmartsev
Evgeniy
E
Eruslanov
Hubert
H
Kübler
Timothy
T
Tseng
Yoshihisa
Y
Sakai
Zhen
Z
Su
Sergei
S
Kaliberov
Axel
A
Heiser
Charles
C
Rosser
Philip
P
Dahm
Dietmar
D
Siemann
Johannes
J
Vieweg
D000818:Animals; D000906:Antibodies / Q000276:immunology; D039481:CD11b Antigen / Q000378:metabolism; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D007680:Kidney Neoplasms / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D022423:Myeloid Cells / Q000378:metabolism*; D009362:Neoplasm Metastasis / Q000473:pathology; D009368:Neoplasm Transplantation; D018384:Oxidative Stress; D013880:Thioredoxin-Disulfide Reductase / Q000378:metabolism; D015854:Up-Regulation; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000276:immunology / Q000378:metabolism*
D000906:Antibodies; D039481:CD11b Antigen; D013880:Thioredoxin-Disulfide Reductase; D040281:Vascular Endothelial Growth Factor Receptor-1