MHC‐II; T‐cells; adenovirus; gene therapy; glioblastoma; tumor organoids; Molecular Medicine; Oncology; Genetics; Cancer Research
Abstract :
[en] The immunosuppressive nature of the tumor microenvironment poses a significant challenge to effective immunotherapies against glioblastoma (GB). Boosting the immune response is critical for successful therapy. Here, we adopted a cancer gene therapy approach to induce T-cell-mediated killing of the tumor through increased activation of the immune system. Patient-based three-dimensional (3D) GB models were infected with a replication-deficient adenovirus (AdV) armed with the class II major histocompatibility complex (MHC-II) transactivator (CIITA) gene (Ad-CIITA). Successful induction of surface MHC-II 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-II expression. Co-culture of infected tumor cells with either peripheral blood mononuclear cells (PBMCs) or isolated T-cells led to dramatic breakdown of GB organoids. Intriguingly, both wild-type and mutant Ad-CIITA, but not unarmed AdV, triggered immune-mediated tumor cell death in the co-culture system, suggesting an at least partially MHC-II-independent process. We further show that the observed cancer cell killing requires the presence of either CD8+ or CD4+ T-cells and direct contact between GB and immune cells. We did not, however, detect evidence of activation of canonical T-cell-mediated cell death pathways. Although the precise mechanism remains to be determined, these findings highlight the potential of AdV-mediated CIITA delivery to enhance T-cell-mediated immunity against GB.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
SALVATO, Ilaria ✱; University of Luxembourg ; NORLUX Neuro-Oncology Laboratory, Department of Cancer Research, Luxembourg Institute of Health (LIH), Luxembourg, Luxembourg ; Laboratory of Oncolytic Virus Immuno-Therapeutics (LOVIT), Department of Cancer Research, Luxembourg Institute of Health (LIH), Luxembourg, Luxembourg
KLEIN, Eliane ✱; University of Luxembourg > Faculty of Science, Technology and Medicine (FSTM) > Department of Life Sciences and Medicine (DLSM) ; NORLUX Neuro-Oncology Laboratory, Department of Cancer Research, Luxembourg Institute of Health (LIH), Luxembourg, Luxembourg
POLI, Aurelie ; University of Luxembourg ; Neuro-Immunology Group, Department of Cancer Research, Luxembourg Institute of Health (LIH), Luxembourg, Luxembourg
Rezaeipour, Mahsa; NORLUX Neuro-Oncology Laboratory, Department of Cancer Research, Luxembourg Institute of Health (LIH), Luxembourg, Luxembourg
Ermini, Luca; NORLUX Neuro-Oncology Laboratory, Department of Cancer Research, Luxembourg Institute of Health (LIH), Luxembourg, Luxembourg
Nosirov, Bakhtiyor; NORLUX Neuro-Oncology Laboratory, Department of Cancer Research, Luxembourg Institute of Health (LIH), Luxembourg, Luxembourg ; Multiomics Data Science Research Group, Department of Cancer Research, Luxembourg Institute of Health (LIH), Luxembourg, Luxembourg
Lipsa, Anuja; NORLUX Neuro-Oncology Laboratory, Department of Cancer Research, Luxembourg Institute of Health (LIH), Luxembourg, Luxembourg
Oudin, Anaïs; NORLUX Neuro-Oncology Laboratory, Department of Cancer Research, Luxembourg Institute of Health (LIH), Luxembourg, Luxembourg
Baus, Virginie; NORLUX Neuro-Oncology Laboratory, Department of Cancer Research, Luxembourg Institute of Health (LIH), Luxembourg, Luxembourg
Dore, Gian Mario; Laboratory of Oncolytic Virus Immuno-Therapeutics (LOVIT), Department of Cancer Research, Luxembourg Institute of Health (LIH), Luxembourg, Luxembourg
COSMA, Antonio ; University of Luxembourg > Faculty of Law, Economics and Finance > Department of Economics and Management > Team Antonio COSMA ; National Cytometry Platform, Translational Medicine Operation Hub, Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg
GOLEBIEWSKA, Anna ; University of Luxembourg ; NORLUX Neuro-Oncology Laboratory, Department of Cancer Research, Luxembourg Institute of Health (LIH), Luxembourg, Luxembourg
MARCHINI, Antonio ✱; University of Luxembourg ; Laboratory of Oncolytic Virus Immuno-Therapeutics (LOVIT), Department of Cancer Research, Luxembourg Institute of Health (LIH), Luxembourg, Luxembourg ; Laboratory of Oncolytic Virus Immuno-Therapeutics, German Cancer Research Center, Heidelberg, Germany
NICLOU, Simone P. ✱; University of Luxembourg > Faculty of Science, Technology and Medicine (FSTM) > Department of Life Sciences and Medicine (DLSM) ; NORLUX Neuro-Oncology Laboratory, Department of Cancer Research, Luxembourg Institute of Health (LIH), Luxembourg, Luxembourg
Fonds National de la Recherche Luxembourg Fonds De La Recherche Scientifique - FNRS
Funding text :
We are grateful for the use of the LIH PRECISION\u2010PDX Brain Tumor Bank ( www.precision\u2010pdx.lu ), supported by the patients, the Neurosurgery Department of the Centre Hospitalier de Luxembourg, the NORLUX Neuro\u2010Oncology Laboratory and the Clinical and Epidemiological Investigation Center of LIH. We thank Prof. Roberto Accolla and Prof. Greta Forlani for providing cell lines and critically reviewing the manuscript, Pilar M. Moreno\u2010Sanchez for technical assistance in the management of PDOXs, and the Luxembourg Croix Rouge and its donors for generously providing healthy donor blood samples. We acknowledge the support from LIH's core facilities (Animal facility, imaging facility, National Cytometry Platform, LUXGEN sequencing platform). We acknowledge the financial support by the Luxembourg Institute of Health, FNRS\u2010T\u00E9l\u00E9vie (GBodImm no. 7.8513.18, GBodImm2 no. 7651720F, ImmoGB 7.8505.20, ImmoGB2 7.6603.22) and the Luxembourg National Research Fund (C20/BM/14646004/GLASSLUX, C21/BM/15739125/DIOMEDES). For the purpose of open access, and in fulfillment of the obligations arising from the FNR grant agreement, the author has applied a Creative Commons Attribution 4.0 International (CC BY 4.0) license to any Author Accepted Manuscript version arising from this submission. In vivo
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