Caforio Matteo

Dottore di ricerca

ciclo: XXXIV


supervisore: Valentina Folgiero
relatore: Fabio DI Domenico

Titolo della tesi: Indolamine 2-3 deoxygenase 1 is involved in Neuroblastoma Immune Escape

Background: Immune escape mechanisms employed by neuroblastoma cells include secretion of immunosuppressive factors disrupting effective antitumor immunity. The use of cellular therapy to treat solid tumors needs to be implemented. Methods: Real Time PCR and Western Blot were performed to analyze gene and protein levels modifications. Transcriptional study was performed by ChIP and luciferase reporter assays upon experiments of mutagenesis on the promoter sequence. Neuroblastoma tissue sample were analyzed by IHC and Real Time PCR to perform correlation study. Killing activity of anti-GD2 Chimeric Antigen Receptor (CAR) T or natural killer (NK) cells against target neuroblastoma cells was assessed through co-culture experiments and quantified by FACS analysis. ELISA assay was used to quantify IFNg secreted by NK and CAR T cells. Results: Inhibition of MYCN expression in neuroblastoma 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 neuroblastoma samples. This finding was supported by the identification of a transcriptional repressive role of MYCN on IDO1 promoter. Furthermore, 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 neurobalstoma, IDO1 is able to inhibit the anti-tumor effect displayed by of both anti-GD2 Chimeric Antigen Receptor (GD2.CAR) T-cell and NK cells, mainly by impairing their IFNγ production. Conclusions: The evidence of IDO1 involvement in neuroblastoma 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.

Produzione scientifica

11573/1634188 - 2022 - CAPE and its synthetic derivative VP961 restore BACH1/NRF2 axis in Down syndrome
Pagnotta, S.; Tramutola, A.; Barone, E.; Di Domenico, F.; Pittala, V.; Salerno, L.; Folgiero, V.; Caforio, M.; Locatelli, F.; Petrini, S.; Butterfield, D. A.; Perluigi, M. - 01a Articolo in rivista
rivista: FREE RADICAL BIOLOGY & MEDICINE (Elsevier Science Limited:Oxford Fulfillment Center, PO Box 800, Kidlington Oxford OX5 1DX United Kingdom:011 44 1865 843000, 011 44 1865 843699, EMAIL: asianfo@elsevier.com, tcb@elsevier.co.UK, INTERNET: http://www.elsevier.com, http://www.elsevier.com/locate/shpsa/, Fax: 011 44 1865 843010) pp. 1-13 - issn: 0891-5849 - wos: WOS:000790734500001 (7) - scopus: 2-s2.0-85126271579 (9)

11573/1474752 - 2020 - Proteomics study of peripheral blood mononuclear cells in down syndrome children
Lanzillotta, C.; Greco, V.; Valentini, D.; Villani, A.; Folgiero, V.; Caforio, M.; Locatelli, F.; Pagnotta, S.; Barone, E.; Urbani, A.; Domenico, F. D.; Perluigi, M. - 01a Articolo in rivista
rivista: ANTIOXIDANTS (Basel: MDPI) pp. 1-27 - issn: 2076-3921 - wos: WOS:000592837500001 (3) - scopus: 2-s2.0-85095984917 (4)

11573/1456191 - 2020 - Chronic perk induction promotes alzheimer-like neuropathology in down syndrome: Insights for therapeutic intervention
Lanzillotta, C.; Zuliani, I.; Tramutola, A.; Barone, E.; Blarzino, C.; Folgiero, V.; Caforio, M.; Valentini, D.; Villani, A.; Locatelli, F.; Butterfield, D. A.; Head, E.; Perluigi, M.; Abisambra, J. F.; Di Domenico, F. - 01a Articolo in rivista
rivista: PROGRESS IN NEUROBIOLOGY (-Oxford:PERGAMON-ELSEVIER SCIENCE LTD, -Oxford; New York; Toronto; Rushcutters Bay; Braunschweig: Pergamon Press Vieweg & Sohn.) pp. 101892- - issn: 0301-0082 - wos: WOS:000604785900004 (16) - scopus: 2-s2.0-85089501564 (19)

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