Abstract Background: Natural killer (NK) cells play a crucial role in cancer immunosurveillance. They infiltrate the tumor microenvironment and kill tumor cells by integrating activating signals from stress-induced ligands on cancer cells and inhibitory signals, mediated by the major histocompatibility immune complex (HLA), that preserve self-tolerance. However, their effectiveness against solid tumors is limited by tumor-driven immune-suppression. Oncolytic viruses (OV) can potentially overcome this barrier by selectively infecting tumor cells and stimulating antitumor immunity. We thus combined the oncolytic adenovirus Delta24-RGD with NK cells to target aggressive solid tumors, aiming to define the mechanisms underlying virus-induced NK cell hyperactivation and supporting clinical translation of this approach. Methods: We conducted in vitro and in vivo studies to evaluate the cytotoxicity of ex vivo-expanded cord blood-derived NK cells against Delta24-RGD-infected pancreatic ductal adenocarcinoma and glioblastoma cells. In vitro, OV-infected tumor cells were co-cultured with NK cells, followed by CyTOF phenotyping and cytotoxicity evaluation using xCelligence and Incucyte. Long-term cytotoxic capacity was assessed by first co-culturing NK cells with OV-infected or non-infected tumor cells, isolating NK cells and then testing their serial killing against fresh tumor targets. In vivo efficacy was tested using patient-derived xenograft glioblastoma mouse models. Mechanistic workup included ATAC-seq, bulk RNA-seq, CUT Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 5194.
Shaim et al. (Fri,) studied this question.