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

Department of Urology, College of Medicine, University of Florida, Gainesville, FL 32610, USA.
The Journal of Immunology (Impact Factor: 4.92). 08/2008; 181(1):346-53. DOI: 10.4049/jimmunol.181.1.346
Source: PubMed


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.

Download full-text


Available from: Sergei Kusmartsev, Sep 29, 2015
81 Reads
  • Source
    • "Osada has then confirmed this result in humans by demonstrating an increase in the number of DCs in peripheral blood and an improvement of DCs functions in advanced solid cancer patients treated with bevacizumab (anti-VEGF-A) (72). Blockade of VEGF-A pathway by anti-VEGF-A antibody in tumor-bearing mice also leads to a significant reduction of MDSCs in peripheral blood, as compared with untreated mice (73). Similarly, a decrease in the absolute number of MDSC in the spleen, bone marrow, and tumor in different tumor models (the MCA26 colorectal cancer, or the Renca renal cancer), has also been observed after treatment with sunitinib (74, 75). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The progressive conversion of normal cells into cancer cells is characterized by the acquisition of eight hallmarks. Among these criteria, the capability of the cancer cell to avoid the immune destruction has been noted. Thus, tumors develop mechanisms to become invisible to the immune system, such as the induction of immunosuppressive cells, which are able to inhibit the development of an efficient immune response. Molecules produced in the tumor microenvironment are involved in the occurrence of an immunosuppressive microenvironment. Recently, it has been shown that vascular endothelial growth factor A (VEGF-A) exhibits immunosuppressive properties in addition to its pro-angiogenic activities. VEGF-A can induce the accumulation of immature dendritic cells, myeloid-derived suppressor cells, regulatory T cells, and inhibit the migration of T lymphocytes to the tumor. Other pro-angiogenic factors such as placental growth factor (PlGF) could also participate in tumor-induced immunosuppression, but only few works have been performed on this point. Here, we review the impact of pro-angiogenic factors (especially VEGF-A) on immune cells. Anti-angiogenic molecules, which target VEGF-A/VEGFR axis, have been developed in the last decades and are commonly used to treat cancer patients. These drugs have anti-angiogenic properties but can also counteract the tumor-induced immunosuppression. Based on these immunomodulatory properties, anti-angiogenic molecules could be efficiently associated with immunotherapeutic strategies in preclinical models. These combinations are currently under investigation in cancer patients.
    Frontiers in Oncology 04/2014; 4:70. DOI:10.3389/fonc.2014.00070
  • Source
    • "Pharmacological interventions, however, showed a marginal impact on DCs with respect to macrophages, which were skewed from an M2 (protumorigenic) toward an M1 (anti-tumor) phenotype. Differentiation toward proinflammatory DCs was induced by vascular endothelial growth factor inhibitors (24) or blockers of chemokines (25). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Dendritic cells (DCs) are central to the adoptive immune response, and their function is regulated by diverse signals in a context-specific manner. Different DCs have been described in physiologic conditions, inflammation, and cancer, prompting a series of questions on how adoptive immune responses, or tolerance, develop against tumors. Increasing evidence suggests that tumor treatments induce a dramatic change on tumor-infiltrating lymphocytes and, in particular, on some DC subtypes. In this review, we summarize the latest evidence on the role of DCs in cancer and preliminary evidence on chemotherapy-associated antigens identified in human cancers.
    Frontiers in Immunology 01/2014; 4:503. DOI:10.3389/fimmu.2013.00503
  • Source
    • "4 S.E.J. Chambers et al. / Immunobiology xxx (2013) xxx– xxx (Kusmartsev et al. 2008 "
    [Show abstract] [Hide abstract]
    ABSTRACT: Macrophage function is not restricted to the innate and adaptive immune responses, but also includes host defence, wound healing, angiogenesis and homeostatic processes. Within the spectrum of macrophage activation there are two extremes: M1 classically activated macrophages which have a pro-inflammatory phenotype, and M2 alternatively activated macrophages which are pro-angiogenic and anti-inflammatory. An important property of macrophages is their plasticity to switch from one phenotype to the other and they can be defined in their polarisation state at any point between the two extremes. In order to determine what stage of activation macrophages are in, it is essential to profile various phenotypic markers for their identification. This review describes the angiogenic role for myeloid cells: circulating monocytes, Tie-2 expressing monocytes (TEMs), myeloid-derived suppressor cells (MDSCs), tumour associated macrophages (TAMs), and neutrophils. Each cell type is discussed by phenotype, roles within angiogenesis and possible targets as a cell therapy. In addition, we also refer to our own research on myeloid angiogenic cells (MACs), outlining their ability to induce angiogenesis and their similarities to alternatively activated M2 macrophages. MACs significantly contribute to vascular repair through paracrine mechanisms as they lack the capacity to differentiate into endothelial cells. Since MACs also retain plasticity, phenotypic changes can occur according to disease states and the surrounding microenvironment. This pro-angiogenic potential of MACs could be harnessed as a novel cellular therapy for the treatment of ischaemic diseases, such as diabetic retinopathy, hind limb ischaemia and myocardial infarction; however, caution needs to be taken when MACs are delivered into an inflammatory milieu.
    Immunobiology 07/2013; 218(11). DOI:10.1016/j.imbio.2013.06.010 · 3.04 Impact Factor
Show more

Similar Publications