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GD2 redirected CAR T and activated NK-cell-mediated secretion of IFNγ overcomes MYCN-dependent IDO1 inhibition, contributing to neuroblastoma cell immune escape.
Caforio, Matteo; Sorino, Cristina; Caruana, Ignazio; Weber, Gerrit; Camera, Antonio; Cifaldi, Loredana; De Angelis, Biagio; Del Bufalo, Francesca; Vitale, Alessia; Goffredo, Bianca Maria; De Vito, Rita; Fruci, Doriana; Quintarelli, Concetta; Fanciulli, Maurizio; Locatelli, Franco; Folgiero, Valentina.
Affiliation
  • Caforio M; Department of Hematology/Oncology and Gene and Cell Therapy, IRCCS Bambino Gesù Children's Hospital, Rome, Italy.
  • Sorino C; Departement of Biochemical Sciences "A Rossi Fanelli", Sapienza University of Rome, Rome, Italy.
  • Caruana I; SAFU Laboratory, Department of Research, Advanced Diagnostic, and Technological Innovation, Istituto Regina Elena Istituto di Ricovero e Cura a Carattere Scientifico, Rome, Italy, Italy.
  • Weber G; Department of Hematology/Oncology and Gene and Cell Therapy, IRCCS Bambino Gesù Children's Hospital, Rome, Italy.
  • Camera A; Department of Hematology/Oncology and Gene and Cell Therapy, IRCCS Bambino Gesù Children's Hospital, Rome, Italy.
  • Cifaldi L; Department of Hematology/Oncology and Gene and Cell Therapy, IRCCS Bambino Gesù Children's Hospital, Rome, Italy.
  • De Angelis B; Academic Department of Pediatrics (DPUO), IRCCS Bambino Gesù Children's Hospistal, Rome, Italy.
  • Del Bufalo F; Department of Clical Sciences and Translational Medicine, University of Tor Vergata, Rome, Italy.
  • Vitale A; Department of Hematology/Oncology and Gene and Cell Therapy, IRCCS Bambino Gesù Children's Hospital, Rome, Italy.
  • Goffredo BM; Department of Hematology/Oncology and Gene and Cell Therapy, IRCCS Bambino Gesù Children's Hospital, Rome, Italy.
  • De Vito R; Division of Metabolism and Research Unit of Metabolic Biochemistry, IRCCS Bambino gesù Children's Hospital, Rome, Italy.
  • Fruci D; Division of Metabolism and Research Unit of Metabolic Biochemistry, IRCCS Bambino gesù Children's Hospital, Rome, Italy.
  • Quintarelli C; Department of Laboratories, Pathology Unit, IRCCS Bambino Gesù Children's Hospital, Rome, Italy.
  • Fanciulli M; Department of Hematology/Oncology and Gene and Cell Therapy, IRCCS Bambino Gesù Children's Hospital, Rome, Italy.
  • Locatelli F; Department of Hematology/Oncology and Gene and Cell Therapy, IRCCS Bambino Gesù Children's Hospital, Rome, Italy.
  • Folgiero V; Departyment of Clinical Medicine and Surgery, Federico II University of Naples, Naples, Italy.
J Immunother Cancer ; 9(3)2021 03.
Article in En | MEDLINE | ID: mdl-33737337
Immune escape mechanisms employed by neuroblastoma (NB) cells include secretion of immunosuppressive factors disrupting effective antitumor immunity. The use of cellular therapy to treat solid tumors needs to be implemented. Killing activity of anti-GD2 Chimeric Antigen Receptor (CAR) T or natural killer (NK) cells against target NB cells was assessed through coculture experiments and quantified by FACS analysis. ELISA assay was used to quantify interferon-γ (IFNγ) secreted by NK and CAR T cells. Real Time PCR and Western Blot were performed to analyze gene and protein levels modifications. Transcriptional study was performed by chromatin immunoprecipitation and luciferase reporter assays on experiments of mutagenesis on the promoter sequence. NB tissue sample were analyzed by IHC and Real Time PCR to perform correlation study. We demonstrate that Indoleamine-pyrrole 2,3-dioxygenase1 (IDO1), due to its ability to convert tryptophan into kynurenines, is involved in NB resistance to activity of immune cells. In NB, IDO1 is able to inhibit the anti-tumor effect displayed by of both anti-GD2 CAR (GD2.CAR) T-cell and NK cells, mainly by impairing their IFNγ production. Furthermore, inhibition of MYCN expression in NB results into accumulation of IDO1 and consequently of kynurenines, which negatively affect the immune surveillance. Inverse correlation between IDO1 and MYCN expression has been observed in a wide cohort of NB samples. This finding was supported by the identification of a transcriptional repressive role of MYCN on IDO1 promoter. The evidence of IDO1 involvement in NB immune escape and its ability to impair NK and GD2.CAR T-cell activity contribute to clarify one of the possible mechanisms responsible for the limited efficacy of these immunotherapeutic approaches. A combined therapy of NK or GD2.CAR T-cells with IDO1 inhibitors, a class of compounds already in phase I/II clinical studies, could represent a new and still unexplored strategy capable to improve long-term efficacy of these immunotherapeutic approaches.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Killer Cells, Natural / Lymphocyte Activation / T-Lymphocytes / Immunotherapy, Adoptive / Interferon-gamma / Indoleamine-Pyrrole 2,3,-Dioxygenase / N-Myc Proto-Oncogene Protein / Receptors, Chimeric Antigen / Gangliosides / Neuroblastoma Type of study: Prognostic_studies Limits: Humans Language: En Journal: J Immunother Cancer Year: 2021 Document type: Article Affiliation country: Italy Country of publication: United kingdom

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Killer Cells, Natural / Lymphocyte Activation / T-Lymphocytes / Immunotherapy, Adoptive / Interferon-gamma / Indoleamine-Pyrrole 2,3,-Dioxygenase / N-Myc Proto-Oncogene Protein / Receptors, Chimeric Antigen / Gangliosides / Neuroblastoma Type of study: Prognostic_studies Limits: Humans Language: En Journal: J Immunother Cancer Year: 2021 Document type: Article Affiliation country: Italy Country of publication: United kingdom