Abstract
Cytokine-inducible SH2-containing protein (CIS; encoded by the gene CISH) is a key negative regulator of interleukin-15 (IL-15) signaling in natural killer (NK) cells. Here, we develop human CISH-knockout (CISH−/−) NK cells using an induced pluripotent stem cell-derived NK cell (iPSC-NK cell) platform. CISH−/− iPSC-NK cells demonstrate increased IL-15-mediated JAK-STAT signaling activity. Consequently, CISH−/− iPSC-NK cells exhibit improved expansion and increased cytotoxic activity against multiple tumor cell lines when maintained at low cytokine concentrations. CISH−/− iPSC-NK cells display significantly increased in vivo persistence and inhibition of tumor progression in a leukemia xenograft model. Mechanistically, CISH−/− iPSC-NK cells display improved metabolic fitness characterized by increased basal glycolysis, glycolytic capacity, maximal mitochondrial respiration, ATP-linked respiration, and spare respiration capacity mediated by mammalian target of rapamycin (mTOR) signaling that directly contributes to enhanced NK cell function. Together, these studies demonstrate that CIS plays a key role to regulate human NK cell metabolic activity and thereby modulate anti-tumor activity.
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•Deletion of CISH in human NK cells leads to improved anti-tumor activity•CISH−/− NK cells demonstrate more efficient glycolytic and OxPhos activity•The improved metabolic profile is mediated by mTOR signaling•CISH−/− NK cells more effectively treat AML in vivo with longer NK cell persistence
CISH normally inhibits IL-15 signaling in natural killer (NK) cells. Here, Zhu and colleagues delete CISH expression in NK cells derived from human induced pluripotent stem cells (iPSCs). CISH−/− iPSC-derived NK cells demonstrate improved killing of tumor cells that is directly attributable to a more efficient metabolic profile.
