Oxidative stress regulates expression of VEGFR1 in myeloid cells: Link to tumor-induced immune suppression in renal cell carcinoma

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

Research output: Contribution to journalArticlepeer-review

160 Scopus citations

Abstract

Mctastatic 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 (VEGFRl)/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)-nonenaI, 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.

Original languageEnglish (US)
Pages (from-to)346-353
Number of pages8
JournalJournal of Immunology
Volume181
Issue number1
DOIs
StatePublished - 2008

Fingerprint Dive into the research topics of 'Oxidative stress regulates expression of VEGFR1 in myeloid cells: Link to tumor-induced immune suppression in renal cell carcinoma'. Together they form a unique fingerprint.

Cite this