LAUSR

Significance We used a genome-wide CRISPR screen to identify regulators of NK cell cytotoxicity. Deletion of TMEM30A was shown to provide protection to cancer cells from NK cell killing. The encoded protein is a subunit of a flippase that transports phospholipids in the plasma membrane and we show that disruption of the gene caused phosphatidylserine accumulation on the outside of the cells. TMEM30A-knock-out cells from various hematological malignancies were more resistant to NK cell killing and we demonstrate that this is due to the interaction between phosphatidylserine and the inhibitory NK cell receptor, TIM-3. TMEM30A mutations are recurrent in lymphomas, and our findings suggest that this may serve as an immuno-evasive strategy in these malignancies.