Targeting CISH enhances natural cytotoxicity receptor signaling and reduces NK cell exhaustion to improve solid tumor immunity

Cytokine inducible SH2-containing protein (CISH) is a natural killer (NK) cell negative regulator of cytokine signaling pathway. To further understand CISH functions in NK cells, we developed a conditional Cish -deficient mouse model in NK cells ( Cish fl/fl Ncr1 Ki/+ ). We detected no developmental or homeostatic difference in NK cells. However, global gene expression of Cish fl/fl Ncr1 Ki/+ NK cells compared to Cish +/+ Ncr1 Ki/+ NK cells revealed upregulation of pathways and genes associated with NK cell cycling and activation. We show that CISH does not only regulate interleukin-15 (IL-15) signaling pathways but also natural cytotoxicity receptors (NCR) pathways. Indeed, CISH protein expression level increases upon NCR triggering. Primed Cish fl/fl Ncr1 Ki/+ NK cells display increased activation upon NCR stimulation. Cish fl/fl Ncr1 Ki/+ NK cells display lower activation thresholds and Cish fl/fl Ncr1 Ki/+ mice are more resistant to tumor metastasis. Remarkably, we found that Cish fl/fl Ncr1 Ki/+ mice were also more resistant to primary breast cancer growth in addition to superior control of spontaneous tumor metastasis. CISH deletion favors NK cell accumulation to the primary tumor, optimizes NK cell killing properties and decreases TIGIT immune checkpoint receptor expression, limiting NK cell exhaustion. Finally, we argue that specifically enhancing NK cell function is sufficient to boost anti-tumor response to both primary and secondary tumor models. Using CRISPRi, we then targeted CISH in human NK-92 or primary NK cells. According to the results in our mouse model, CISH deletion favors NCR signaling and anti-tumor functions in human NK cells. Our results validate CISH as an emerging therapeutic target to enhance NK cell immunotherapy.