Characterization of CISH-knockout NK cells derived from human peripheral blood and evaluated the antitumor effects in allogeneic glioblastoma

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Presentation Time: 11:30 AM - 12:45 PM
Poster Board Number: B945
Abstract ID: 6154

Presenting Author:
Tsutomu Nakazawa , Leader of Basic Research Group at Nara Med. Univ., Grandsoul Res. Inst. for Immunol.

Abstract:

Background: Glioblastoma (GBM) is the most common malignant brain tumor. Allogeneic natural killer cells (NKCs) have gained considerable attention as promising immunotherapeutic tools against cancer, where gene-edited NKCs would result in effective anti-cancer treatment. This study focused on the immune checkpoint molecule cytokine-inducible SH2-containing protein (CISH) as a critical negative regulator in NKCs.

Methods:  We generated human primary CISH-deleted NKCs (NKC dCISH) by combining our specific NKC expansion method and CRISPR/Cas9. The genome-edited NKCs underwent microarray analysis. The anti-GBM activity of the genome-edited NKCs was evaluated in vitro and further detected in vivo antitumor effects using xenograft brain tumor mice.

Results: We successfully induced NKC dCISH derived from human peripheral blood. Gene set enrichment analysis (GSEA) using microarrays revealed that the enriched genes were involved in effector functions in NKC dCISH. CISH deletion enhanced NKC-mediated apoptosis induction against allogeneic GBM cells and spheroids. Intracranial administration of the allogeneic CISH-deleted NKCs prolonged the overall survival of xenograft brain tumor mice. 

Conclusion:  CISH deletion enhanced NKCs' effector functions and NKC-mediated antitumor effects in allogeneic GBM. The genome-editing NKCs could be a promising immunotherapeutic alternative for patients with GBM.