Adenoviral Delivery of the CIITA Transgene Induces T-Cell-Mediated Killing in Glioblastoma Organoids

Abstract

ABSTRACTThe immunosuppressive nature of the microenvironment poses significant challenges in developing effective immunotherapies against glioblastoma (GBM). Enhancing immune-mediated responses is a prerequisite for a successful therapy. Here, we present a cancer gene therapy approach utilizing a replication-deficient adenovirus (AdV) armed with the Class II Major Histocompatibility Complex (MHC-II) TransactivatorCIITAgene (Ad-CIITA) to induce antigen-presenting properties in GBM cells. Successful induction of MHC-II molecules at the cell membrane was achieved in infected GBM cell lines and primary human GBM organoids. Infection with an AdV carrying a mutant form ofCIITAresulted in cytoplasmic accumulation of CIITA without subsequent MHC-II expression. Intriguingly, both wild-type and mutant Ad-CIITA triggered prominent immune-mediated tumor cell death in a co-culture system with primary human GBM organoids, suggesting a partially MHC-II-independent process. We further show that the observed cancer cell killing requires the presence of T-cells and direct contact between GBM and immune cells. Overall, these findings highlight that AdV-mediatedCIITAdelivery enhances T-cell-mediated immunity against GBM, the precise mechanism of which remains to be elucidated.