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Oxidative Stress Regulates Expression of VEGFR1 in Myeloid Cells: Link to Tumor-Induced Immune Suppression in Renal Cell Carcinoma¹

Sergei Kusmartsev^2,*, Evgeniy Eruslanov^*, Hubert Kübler^*, Timothy Tseng, Yoshihisa Sakai^*, Zhen Su^*, Sergei Kaliberov, Axel Heiser^*, Charles Rosser^*, Philip Dahm^*, Dietmar Siemann and Johannes Vieweg^*

^* Department of Urology, College of Medicine and Department of Pharmacology and Experimental Therapeutics, University of Florida, Gainesville, FL 32610; Department of Surgery, Duke University, Durham, NC 27710; and Department of Radiation Oncology, University of Alabama, Birmingham, AL 35294

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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by grants from the Department of Health, Florida Biomedical Research Program (to S.K.) and the National Cancer Institute (to J.V.).

² Address correspondence and reprint requests to Dr. Sergei Kusmartsev, University of Florida, Cancer and Genetics Research Center, 1376 Mowry Road, Room 459, P.O. Box 103633, Gainesville, FL 32610. E-mail address: s.kusmartsev{at}urology.ufl.edu

³ Abbreviations used in this paper: RCC, renal cell carcinoma; BSO, L-buthionine-(S,R)-sulfoximine; DC, dendritic cell; DCNB, 1,2-dichloro-4-nitrobenzene; 4-HNE, 4-hydroxy-2(E)-nonenal; GSH, glutathione; GSH-ME, glutathione methylester; VEGF, vascular endothelial growth factor; VEGFR1, VEGF receptor 1; VHL, von Hippel-Lindau.