Oxidative stress regulates expression of VEGFR1 in myeloid cells: link to tumor-induced immune suppression in renal cell carcinoma.
ISBN or ISSN
Journal of immunology (Baltimore, Md. : 1950)
Publication Date / Copyright Date
American Association of Immunologists
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.
Medicine and Health Sciences
Animals, Antibodies, CD11b Antigen, Cells, Cultured, Female, Humans, Kidney Neoplasms, Mice, Myeloid Cells, Neoplasm Metastasis, Neoplasm Transplantation, Oxidative Stress, Thioredoxin-Disulfide Reductase, Up-Regulation, Vascular Endothelial Growth Factor Receptor-1
Kusmartsev, Sergei; Eruslanov, Evgeniy; Kübler, Hubert; Tseng, Timothy; Sakai, Yoshihisa; Su, Zhen; Kaliberov, Sergei; Heiser, Axel; Rosser, Charles; Dahm, Philip; Siemann, Dietmar; and Vieweg, Johannes, "Oxidative stress regulates expression of VEGFR1 in myeloid cells: link to tumor-induced immune suppression in renal cell carcinoma." (2008). NSU-MD Faculty Articles. 44.