Oncotarget

Research Papers:

Glioblastoma progression is assisted by induction of immunosuppressive function of pericytes through interaction with tumor cells

Rut Valdor _, David García-Bernal, Carlos Bueno, Mónica Ródenas, José M. Moraleda, Fernando Macian and Salvador Martínez

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Oncotarget. 2017; 8:68614-68626. https://doi.org/10.18632/oncotarget.19804

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Abstract

Rut Valdor1,2, David García-Bernal3, Carlos Bueno2, Mónica Ródenas2, José M. Moraleda1,3, Fernando Macian4 and Salvador Martínez5

1Internal Medicine Department, Medicine School, University of Murcia, Murcia, Spain

2Brain Regionalization and Development Gene Unit, Biomedical Research Institute of Murcia (IMIB-Arrixaca), Murcia, Spain

3Hematopoietic Transplant and Cellular Therapy Unit, Hematology Service, Virgen de la Arrixaca Clinical University Hospital, Biomedical Research Institute of Murcia (IMIB-Arrixaca), Murcia, Spain

4Department of Pathology, Institute for Aging Studies, Albert Einstein College of Medicine, Bronx, New York, USA

5Instituto de Neurociencias CSIC-UMH and Human Anatomy Department, Instituto de Neurociencias CSIC-UMH, School of Medicine, University Miguel Hernandez, CIBERSAM of ISCIII, Alicante, Spain

Correspondence to:

Salvador Martínez, email: smartinez@umh.es

Rut Valdor, email: rut.valdor@um.es

Keywords: glioblastoma multiforme, brain perivascular cells, tumor, immunotolerance, T cells

Received: March 15, 2017    Accepted: July 11, 2017    Published: August 02, 2017

ABSTRACT

The establishment of immune tolerance during Glioblastoma Multiforme (GBM) progression, is characterized by high levels expression of anti-inflammatory cytokines, which suppress the function of tumor assocciated myeloid cells, and the activation and expansion of tumor antigen specific T cells. However, the mechanisms underlying the failed anti-tumor immune response around the blood vessels during GBM, are poorly understood. The consequences of possible interactions between cancer cells and the perivascular compartment might affect the tumor growth. In this work we show for the first time that GBM cells induce immunomodulatory changes in pericytes in a cell interaction-dependent manner, acquiring an immunosuppresive function that possibly assists the evasion of the anti-tumor immune response and consequently participates in tumor growth promotion. Expression of high levels of anti-inflammatory cytokines was detected in vitro and in vivo in brain pericytes that interacted with GBM cells (GBC-PC). Furthermore, reduction of surface expression of co-stimulatory molecules and major histocompatibility complex molecules in GBC-PC correlated with a failure of antigen presentation to T cells and the acquisition of the ability to supress T cell responses. In vivo, orthotopic xenotransplant of human glioblastoma in an immunocompetent mouse model showed significant GBM cell proliferation and tumor growth after the establishment of interspecific immunotolerance that followed GMB interaction with pericytes.


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