A forward genetic screen reveals novel independent regulators of ULBP1, an activating ligand for natural killer cells

Cancer is caused by a series of mutations that result in uncontrolled cell growth and division. Yet, the body's immune system can often detect and destroy abnormal cells before they cause tumors and disease. Natural killer cells are part of the immune system and have receptors on their surface that allow them to tell the difference between healthy host cells and host cells that are stressed or abnormal. Some of these receptors activate the natural killer cells when they bind to their target molecules. Other receptors have the opposite effect and inhibit the natural killer cells. Activation occurs when the signaling from the activating receptors is stronger than the signals from the inhibitory receptors. One of the well-studied activating receptors recognizes a number of proteins and molecules that are produced by abnormal or tumor cells, including a protein called ULBP1. This protein is absent from the surface of healthy cells but is found in abundance on tumor cells. However, it is still not clear what drives tumor cells to produce ULBP1 (or other molecules) that are recognized by natural killer cell receptors. Now, Gowen et al. report on a genetic screen that has revealed numerous genes that regulate the levels of ULBP1 in human cells. Many of these genes had independent effects that when added together accounted for most of the ULBP1 present on the cell surface. Gowen et al. then explored some of the ‘regulators’ encoded by these genes in more detail. One called ATF4, which had previously been linked to stress responses, was shown to increase the expression of the gene for ULBP1 in cancer cells. Another regulator called RBM4 instead acted in a different way and at a later stage in ULBP1 production. All together, these findings offer insight into the stress pathways that alert the immune system to abnormal cells. The next challenge will be investigating how these pathways might be exploited for cancer immunotherapy.