title: IDO1 involvement in mTOR pathway: a molecular mechanism of resistance to mTOR targeting in medulloblastoma.
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.
authors.affiliation: Department of Hematology/Oncology and Stem Cell Transplantation, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Folgiero
authors.affiliation: Department of Molecular Medicine, Sapienza University, Rome, Italy.|Center for Life NanoScience@Sapienza, Istituto Italiano di Tecnologia, Rome, Italy.
authors.forename: Evelina
authors.initials: E
authors.lastname: Miele
authors.affiliation: Department of Neuroscience and Neurorehabilitation, Neurosurgery Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Carai
authors.affiliation: Department of Molecular Medicine, Sapienza University, Rome, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Ferretti
authors.affiliation: Department of Molecular Medicine, Sapienza University, Rome, Italy.|Center for Life NanoScience@Sapienza, Istituto Italiano di Tecnologia, Rome, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Alfano
authors.affiliation: Department of Molecular Medicine, Sapienza University, Rome, Italy.
authors.forename: Agnese
authors.initials: A
authors.lastname: Po
authors.affiliation: Department of Hematology/Oncology and Stem Cell Transplantation, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Bertaina
authors.affiliation: Department of Laboratory Medicine, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
authors.forename: Bianca Maria
authors.initials: BM
authors.lastname: Goffredo
authors.affiliation: Department of Laboratories, Pathology Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
authors.forename: Maria Chiara
authors.initials: MC
authors.lastname: Benedetti
authors.affiliation: Department of Laboratories, Pathology Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
authors.forename: Francesca Diomedi
authors.initials: FD
authors.lastname: Camassei
authors.affiliation: Department of Hematology/Oncology and Stem Cell Transplantation, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Cacchione
authors.affiliation: Department of Hematology/Oncology and Stem Cell Transplantation, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.|Department of Pediatric Science, University of Pavia, Pavia, Italy.
authors.forename: Franco
authors.initials: F
authors.lastname: Locatelli
authors.affiliation: Department of Hematology/Oncology and Stem Cell Transplantation, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Mastronuzzi
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000627:therapeutic use; D045744:Cell Line, Tumor; D002528:Cerebellar Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D002648:Child; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000235:genetics* / Q000378:metabolism; D007223:Infant; D008527:Medulloblastoma / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D058990:Molecular Targeted Therapy; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics*; D020123:Sirolimus / Q000627:therapeutic use; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D059016:Tumor Microenvironment / Q000187:drug effects / Q000235:genetics / Q000276:immunology
chemical_list: D000903:Antibiotics, Antineoplastic; C576710:IDO1 protein, human; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus
keywords: CCL2; IDO1; MB; Treg; mTOR