Metabolic Reprograming Due to Deletion of <i>CISH</i> in Human Natural Killer Cells Promotes <i>in vivo</i> Persistence and Enhances Anti-Tumor Activity

• DOI: 10.2139/ssrn.3544410
• Publication Date: 2020-03-04T06:31:22Z
• Authors: Huang Zhu; Robert H. Blum; Davide Bernareggi; Eivind Heggernes Ask; Zhengming Wu; Hanna Julie Hoel; Zhipeng Meng; Chengsheng Wu; Kun-Liang Guan; Karl-Johan Malmberg; Dan S. Kaufman
• Keywords: Persistence (discontinuity)

Cytokine-inducible SH2-containing protein (CIS, encoded by the gene CISH) is a key negative regulator of IL-15 signaling in natural killer (NK) cells. Here, we developed human CISH knockout (CISH-/-) NK cells using an induced pluripotent stem cell-derived cell (iPSC-NK cell) platform. CISH-/- iPSC-derived demonstrate increased mediated JAK-STAT pathway activity. Consequently iPSC-NK exhibit improved expansion and cytotoxic activity against multiple tumor lines when maintained at low cytokine concentration. display significantly vivo persistence inhibition progression leukemia xenograft model. Mechanistically, metabolic fitness characterized significant increase basal glycolysis, glycolytic capacity, maximal mitochondrial respiration, ATP-linked respiration spare capacity which are mTOR directly contribute to enhanced function. In addition, that deletion increases single-cell polyfunctionality secreting effector cytokines, profile has been proven be positively associated with clinical outcome CAR-T Together, these studies CIS plays role regulate leads anti-tumor