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Boosting the immune response is critical for successful therapy. Here, we adopted a cancer gene therapy approach to induce T\u2010cell\u2010mediated killing of the tumor through increased activation of the immune system. Patient\u2010based three\u2010dimensional (3D) GB models were infected with a replication\u2010deficient adenovirus (AdV) armed with the class II major histocompatibility complex (MHC\u2010II) transactivator (\n                    <jats:italic>CIITA<\/jats:italic>\n                    ) gene (Ad\u2010CIITA). Successful induction of surface MHC\u2010II was achieved in infected GB cell lines and primary human GB organoids. Infection with an AdV carrying a mutant form of CIITA with a single amino acid substitution resulted in cytoplasmic accumulation of CIITA without subsequent MHC\u2010II expression. Co\u2010culture of infected tumor cells with either peripheral blood mononuclear cells (PBMCs) or isolated T\u2010cells led to dramatic breakdown of GB organoids. Intriguingly, both wild\u2010type and mutant Ad\u2010CIITA, but not unarmed AdV, triggered immune\u2010mediated tumor cell death in the co\u2010culture system, suggesting an at least partially MHC\u2010II\u2010independent process. We further show that the observed cancer cell killing requires the presence of either CD8\n                    <jats:sup>+<\/jats:sup>\n                    or CD4\n                    <jats:sup>+<\/jats:sup>\n                    T\u2010cells and direct contact between GB and immune cells. We did not, however, detect evidence of activation of canonical T\u2010cell\u2010mediated cell death pathways. Although the precise mechanism remains to be determined, these findings highlight the potential of AdV\u2010mediated\n                    <jats:italic>CIITA<\/jats:italic>\n                    delivery to enhance T\u2010cell\u2010mediated immunity against GB.\n                  <\/jats:p>","DOI":"10.1002\/1878-0261.13750","type":"journal-article","created":{"date-parts":[[2024,11,13]],"date-time":"2024-11-13T07:32:15Z","timestamp":1731483135000},"page":"682-697","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Adenoviral delivery of the\n                    <i>CIITA<\/i>\n                    transgene induces T\u2010cell\u2010mediated killing in glioblastoma organoids"],"prefix":"10.1002","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9659-2703","authenticated-orcid":false,"given":"Ilaria","family":"Salvato","sequence":"first","affiliation":[{"name":"NORLUX Neuro\u2010Oncology Laboratory, Department of Cancer Research Luxembourg Institute of Health (LIH)  Luxembourg Luxembourg"},{"name":"Laboratory of Oncolytic Virus Immuno\u2010Therapeutics (LOVIT), Department of Cancer Research Luxembourg Institute of Health (LIH)  Luxembourg Luxembourg"},{"name":"Department of Life Sciences and Medicine, Faculty of Science, Technology and Medicine (FSTM) University of Luxembourg  Esch\u2010sur\u2010Alzette Luxembourg"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eliane","family":"Klein","sequence":"additional","affiliation":[{"name":"NORLUX Neuro\u2010Oncology Laboratory, Department of Cancer Research Luxembourg Institute of Health (LIH)  Luxembourg Luxembourg"},{"name":"Department of Life Sciences and Medicine, Faculty of Science, Technology and Medicine (FSTM) University of Luxembourg  Esch\u2010sur\u2010Alzette Luxembourg"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aur\u00e9lie","family":"Poli","sequence":"additional","affiliation":[{"name":"Neuro\u2010Immunology Group, Department of Cancer Research Luxembourg Institute of Health (LIH)  Luxembourg Luxembourg"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mahsa","family":"Rezaeipour","sequence":"additional","affiliation":[{"name":"NORLUX Neuro\u2010Oncology Laboratory, Department of Cancer Research Luxembourg Institute of Health (LIH)  Luxembourg Luxembourg"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luca","family":"Ermini","sequence":"additional","affiliation":[{"name":"NORLUX Neuro\u2010Oncology Laboratory, Department of Cancer Research Luxembourg Institute of Health (LIH)  Luxembourg Luxembourg"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bakhtiyor","family":"Nosirov","sequence":"additional","affiliation":[{"name":"NORLUX Neuro\u2010Oncology Laboratory, Department of Cancer Research Luxembourg Institute of Health (LIH)  Luxembourg Luxembourg"},{"name":"Multiomics Data Science Research Group, Department of Cancer Research Luxembourg Institute of Health (LIH)  Luxembourg Luxembourg"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anuja","family":"Lipsa","sequence":"additional","affiliation":[{"name":"NORLUX Neuro\u2010Oncology Laboratory, Department of Cancer Research Luxembourg Institute of Health (LIH)  Luxembourg Luxembourg"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana\u00efs","family":"Oudin","sequence":"additional","affiliation":[{"name":"NORLUX Neuro\u2010Oncology Laboratory, Department of Cancer Research Luxembourg Institute of Health (LIH)  Luxembourg Luxembourg"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Virginie","family":"Baus","sequence":"additional","affiliation":[{"name":"NORLUX Neuro\u2010Oncology Laboratory, Department of Cancer Research Luxembourg Institute of Health (LIH)  Luxembourg Luxembourg"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gian Mario","family":"Dore","sequence":"additional","affiliation":[{"name":"Laboratory of Oncolytic Virus Immuno\u2010Therapeutics (LOVIT), Department of Cancer Research Luxembourg Institute of Health (LIH)  Luxembourg Luxembourg"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio","family":"Cosma","sequence":"additional","affiliation":[{"name":"National Cytometry Platform, Translational Medicine Operation Hub Luxembourg Institute of Health  Esch\u2010sur\u2010Alzette Luxembourg"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Golebiewska","sequence":"additional","affiliation":[{"name":"NORLUX Neuro\u2010Oncology Laboratory, Department of Cancer Research Luxembourg Institute of Health (LIH)  Luxembourg Luxembourg"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3157-4552","authenticated-orcid":false,"given":"Antonio","family":"Marchini","sequence":"additional","affiliation":[{"name":"Laboratory of Oncolytic Virus Immuno\u2010Therapeutics (LOVIT), Department of Cancer Research Luxembourg Institute of Health (LIH)  Luxembourg Luxembourg"},{"name":"Laboratory of Oncolytic Virus Immuno\u2010Therapeutics German Cancer Research Center  Heidelberg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3417-9534","authenticated-orcid":false,"given":"Simone P.","family":"Niclou","sequence":"additional","affiliation":[{"name":"NORLUX Neuro\u2010Oncology Laboratory, Department of Cancer Research Luxembourg Institute of Health (LIH)  Luxembourg Luxembourg"},{"name":"Department of Life Sciences and Medicine, Faculty of Science, Technology and Medicine (FSTM) University of Luxembourg  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