IB-06 * THE ROLE OF TGF IN NK CELL-MEDIATED CYTOTOXICITY IN MEDULLOBLASTOMA

Abstract

Medulloblastoma is the most common pediatric central nervous system (CNS) malignancy, with generally favorable outcomes depending on the molecular subtype. However, recurrent/relapsed disease portends a dismal prognosis. Therefore, novel, innovative, and safe therapies are needed to treat such tumors and to minimize treatment-related morbidities. Immune cell therapy is an appealing, targeted approach for CNS tumors. Natural killer (NK) cells are CD56 + /CD3- cytotoxic lymphocytes that possess the ability to target tumor cells without prior exposure to the tumor. Previous limitations on the use of NK cells in adoptive cell therapy included obtaining sufficient cell numbers for clinical use. We developed a robust expansion platform that enables the growth of large numbers of NK cells that are effective for clinical use. We show that expanded NK cells can induce cytotoxicity of medulloblastoma. However, there is evidence that tumor derived factors could dampen NK cell cytotoxicity in a clinical setting. One mechanism by which medulloblastoma cells may evade NK cell-mediated killing is secretion of transforming growth factor beta (TGFβ), by the tumor itself as well as by the surrounding milieu. We show that NK cells express TGFβ receptor family members, and that NK cell-mediated cytotoxicity is diminished in the presence of soluble TGFβ. This suggests a possible role of TGFβ in immune suppression. We have identified populations of NK cells that variably express the TGFβ receptor and will overcome resistance to TGFβ-induced immunosuppression. Further studies will explore the mechanisms by which NK cells can escape immunosuppression. An understanding of how NK cells can overcome immunosuppression by medulloblastoma may lead to a pre-clinical model of NK cell cytotoxicity in medulloblastoma, as well as shed light on the use of NK cell adoptive therapy in other pediatric CNS malignancies.