Cord blood natural killer cells expressing a dominant negative TGF-β receptor: Implications for adoptive immunotherapy for glioblastoma

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• 作者：Eric S. Yvon¹ ; Rachel Burga² ; Allison Powell² ; Conrad R. Cruz² ; Rohan Fernandes² ; Cecilia Barese² ; Tuongvan Nguyen¹ ; Mohamed S. Abdel-Baki³ ; Catherine M. Bollard² ; ^{cbollard@cnmc.org}
• 关键词：cord blood natural killer cells ; dominant negative receptor ; glioma ; immunotherapy ; TGF-β
• 刊名：Cytotherapy
• 出版年：2017
• 出版时间：March 2017
• 年：2017
• 卷：19
• 期：3
• 页码：408-418
• 全文大小：1186 K
• 卷排序：19

文摘

Cord blood (CB) natural killer (NK) cells are promising effector cells for tumor immunotherapy but are currently limited by immune-suppressive cytokines in the tumor microenvironment, such as transforming growth factor (TGF-β). We observed that TGF-β inhibits expression of activating receptors such as NKG2D and DNAM1 and decreases killing activity against glioblastoma tumor cells through inhibition of perforin secretion. To overcome the detrimental effects of TGF-β, we engrafted a dominant negative TGF-β receptor II (DNRII) on CB-derived NK cells by retroviral transduction and evaluated their ability to kill glioblastoma cells in the presence of TGF-β. After manufacture using Good Manufacturing Practice–compliant methodologies and transduction with DNRII, CB-derived DNRII-transduced NK cells expanded to clinically relevant numbers and retained both their killing ability and their secretion of interferon-γ upon activation. More important, these cells maintained both perforin expression and NKG2D/DNMA1 expression in the presence of TGF-β allowing for recognition and killing of glioblastoma tumor cells. Hence, NK cells expressing a DNRII should have a functional advantage over unmodified NK cells in the presence of TGF-β-secreting tumors and may be an important therapeutic approach for patients with cancer.