Dual targeting of CD155/TIGIT and PD-L1/PD-1 immune checkpoints potentiates NK cell-mediated cytotoxicity in medulloblastoma

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 approximately 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 dual immune checkpoint inhibition can be used as a novel targeted therapy in MB. Methods We utilized single cell and single nuclei sequencing datasets of primary MB tumors, established Group 3 and Sonic Hedgehog MB cell lines and MB patient-derived xenograft (PDX) organoid models, and primary patient-derived MB tissue of all subtypes to study immune checkpoints and their blockade to target MB. Results We identified the expression of immune checkpoint protein CD155 on MB tumor cells and the expression of its inhibitory binding partner TIGIT on immune cells of MB 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 or interferon-γ as a putative immune evasive strategy. Subsequent immunotherapeutic interventions with FDA-approved antibodies Tiragolumab (anti-TIGIT), Durvalumab (anti-PD-1), and their combination potentiated primary NK cell activation and killing of MB cell lines and PDX-derived MB organoids. Conclusion These data propose a translatable and novel immunotherapeutic strategy for children diagnosed with subgroups Sonic Hedgehog and Group 3 MB.