Medulloblastoma rendered susceptible to NK-cell attack by TGFß neutralization

Abstract

Background & Aim Medulloblastoma (MB), the most common pediatric brain cancer, presents with a poor prognosis in patients with high-risk disease, and traditional therapies often cause significant permanent morbidity. Cord blood (CB) natural killer (NK) cells may be promising off-the-shelf effector cells for immunotherapy because they recognize malignant cells without the need for a known target, they are readily available from multiple banks, and they expand to significant numbers. However, they are currently limited by immune suppressive cytokines secreted in the MB tumor microenvironment, such as Transforming Growth Factor β (TGF-β). Methods, Results & Conclusion To overcome the detrimental effects of TGF-β, we modified CB-derived NK cells to express a dominant negative TGF-β receptor II (DNRII) by retroviral transduction and evaluated their ability to kill a TGF-β-secreting MB cell line (Daoy). We observed that the cytotoxic ability of nontransduced CB-NK cells was reduced in the presence ofmedulloblastoma-conditioned, TGF-β-richmedia (decreasing to 14.9±2.1% killing at an E:T ratio of 5:1 from 25.1±2.9%, n=10, p Hence, CB NK cells expressing a TGF-β DNRII may have a functional advantage over unmodified NK cells in the presence of TGF-β-rich MB, warranting further investigation as a novel therapeutic for the treatment of patients with high-risk medulloblastoma.