P08.09.A COMBINED TARGETING OF TIGIT/LAG-3/PD-L1 IMMUNE CHECKPOINTS POTENTIATES NK CELL-MEDIATED CYTOTOXICITY IN MEDULLOBLASTOMA ORGANOIDS

Abstract BACKGROUND 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. MATERIAL AND METHODS 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. RESULTS We identified the expression of immune checkpoint proteins TIGIT/LAG-3/PD-1 on immune cells and their respective high-affinity ligands CD155/MHCII/PD-L1 in MB patient-derived tissues, cell lines, and PDX MB organoids. In addition, while MB shows weak, if any, PD-L1/MHCII protein expression, we found that MB cells can upregulate PD-L1/MHCII expression upon stimulation by natural killer (NK) cells via interferon-γ as a putative immune evasive strategy. Whereas immunotherapeutic interventions with FDA-approved antibodies tiragolumab (anti-TIGIT), durvalumab (anti-PD-L1), or relatlimab (anti-LAG-3) showed minor effects, combinations thereof significantly potentiated primary NK cell activation and killing of MB cell lines and PDX-derived MB organoids. CONCLUSION These data suggest translatable and novel immunotherapeutic strategies for patients diagnosed with MB.