IMPS-18OVERCOMING TGFβ-MEDIATED SUPPRESSION OF NK CELL 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, current therapies have significant long-term neurologic morbidities, and recurrent/relapsed disease portends a dismal prognosis. Therefore, novel, innovative, and safe therapies are needed. Immune cell therapy is an appealing, targeted approach, and NK cells have shown activity against some adult CNS tumors. However, NK cell adoptive cell therapy may be susceptible to the immunosuppressive effects of TGFβ, either produced by the tumor or the surrounding microenvironment. We have developed a robust expansion platform that yields NK cells in sufficient numbers and cyotoxic potency for therapy. We now seek to overcome TGFβ-mediated suppression to enhance NK cell cytotoxicity for CNS tumors. We show that expanded NK cells are highly cytotoxic against medulloblastoma cell lines, but have diminished cytotoxicity toward medulloblastoma in the presence of soluble TGFβ. The decrease in cytotoxicity correlates with a decrease in NKG2D expression on the expanded NK cells, as has been described for freshly-obtained peripheral blood NK cells. However, we also show that NK cells can be expanded in the presence of TGFβ without affecting their proliferative rate, and that the presence of TGFβ alters the CD16 and KIR expression profile, while maintaining NKG2D levels. Furthermore, NK cells that are expanded in the presence of TGFβ are resistant to the immunosuppressive effects of additional TGFβ. We are also exploring genetic and pharmacologic approaches to generating TGFβ-resistance. Understanding the mechanisms of NK cell immunosuppression by medulloblastoma may lead to a better understanding of the disease, and improved pre-clinical models and clinical trials of NK cell adoptive therapy for medulloblastoma and other pediatric CNS malignancies.