Oncotarget

Research Papers:

IDO1 involvement in mTOR pathway: a molecular mechanism of resistance to mTOR targeting in medulloblastoma

Valentina Folgiero _, Evelina Miele, Andrea Carai, Elisabetta Ferretti, Vincenzo Alfano, Agnese Po, Valentina Bertaina, Bianca Maria Goffredo, Maria Chiara Benedetti, Francesca Diomedi Camassei, Antonella Cacchione, Franco Locatelli and Angela Mastronuzzi

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Oncotarget. 2016; 7:52900-52911. https://doi.org/10.18632/oncotarget.9284

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Abstract

Valentina Folgiero1, Evelina Miele2,3, Andrea Carai4, Elisabetta Ferretti2, Vincenzo Alfano2,3, Agnese Po2, Valentina Bertaina1, Bianca Maria Goffredo5, Maria Chiara Benedetti6, Francesca Diomedi Camassei6, Antonella Cacchione1, Franco Locatelli1,7,*, Angela Mastronuzzi1,*

1Department of Hematology/Oncology and Stem Cell Transplantation, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy

2Department of Molecular Medicine, Sapienza University, Rome, Italy

3Center for Life NanoScience@Sapienza, Istituto Italiano di Tecnologia, Rome, Italy

4Department of Neuroscience and Neurorehabilitation, Neurosurgery Unit, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy

5Department of Laboratory Medicine, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy

6Department of Laboratories, Pathology Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy

7Department of Pediatric Science, University of Pavia, Pavia, Italy

*These authors contributed equally to this work

Correspondence to:

Valentina Folgiero, email: valentina.folgiero@opbg.net

Keywords: mTOR, IDO1, Treg, MB, CCL2

Received: February 22, 2016     Accepted: April 11, 2016     Published: May 11, 2016

ABSTRACT

Medulloblastoma (MB) is the most common malignant brain tumor in children. Despite therapeutic advancements, high-risk groups still present significant mortality. A deeper knowledge of the signaling pathways contributing to MB formation and aggressiveness would help develop new successful therapies. The target of rapamycin, mTOR signaling, is known to be involved in MB and is already targetable in the clinical setting. Furthermore, mTOR is a master metabolic regulator able to control cell growth versus autophagy decisions in conditions of amino-acid deprivation that can be due to IDO1 enzymatic activity. IDO1 has been also implicated in the regulation of inflammation, as well as of T cell-mediated immune responses, in a variety of pathological conditions, including brain tumors. In particular, IDO1 induces expansion of regulatory T-cells (Treg), preventing immune response against tumor cells. Analysis of 27 MB tissue specimens for the expression of both mTOR and IDO1 showed their widespread expression in all samples. Testing their cooperation in vitro, a significant involvement of IDO1 in mTOR immunogenic pathway was found, able to counteract the aim of rapamycin treatment. In MB cell lines, inhibition of mTOR strongly induced IDO1 expression and activity, corroborating its ability to recruit Treg cells in the tumor microenvironment. The mTOR/IDO1 cross talk was found to be strictly specific of MB cells. We demonstrated that mTOR pathway cross talks with IDO1 pathway to promote MB immune escape, possibly contributing to failure of mTOR- targeted therapy.


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