EXTH-32. DUAL TARGETING OF CD155/TIGIT AND PD-L1/PD-1 IMMUNE CHECKPOINTS POTENTIATES NATURAL KILLER CELL-MEDIATED CYTOTOXICITY IN MEDULLOBLASTOMA

Abstract Medulloblastoma (MB) is one of the most prevalent pediatric brain malignancies and makes up approximately 20% of all primary brain tumors in children. Current treatment options are not curative for about 30% of patients and leave survivors with an impaired quality of life. Immune checkpoint inhibition can offer a novel targeted therapy but largely remains understudied in MB. The aim of this study was to determine whether immune checkpoint inhibition can be used as a novel targeted therapy in MB. We used MB cell lines, MB patient-derived xenograft (PDX) organoid models, and primary patient-derived MB tissue to study immune checkpoints and their blockade to target MB. We identified the expression of immune checkpoint protein TIGIT on immune cells and its high-affinity ligand CD155 in medulloblastoma patient-derived tissues, cell lines, and PDX MB organoids. In addition, while MB shows weak, if any, PD-L1 protein expression, we found that MB cells can upregulate PD-L1 expression upon stimulation by natural killer (NK) cells via interferon-γ as a putative immune evasive strategy. Subsequent immunotherapeutic interventions with FDA-approved antibodies Tiragolumab (anti-TIGIT), Durvalumab (anti-PD-L1), and their combination potentiated primary NK cell activation and killing of MB cell lines and PDX-derived MB organoids. These data propose a translatable and novel immunotherapeutic strategy for patients diagnosed with MB.