An urgent question for cancer scientists is why immunotherapy achieves dramatic results in some cases but doesn’t help most patients. A recent article outlines independent discoveries, led by two research groups from the Dana-Farber Cancer Institute and published in Science, of a genetic mechanism in cancer cells that influences their response to immunotherapy drugs known as checkpoint inhibitors. While one of the groups focused on clinical trial patients with advanced kidney cancer treated with checkpoint inhibitors, the other group, led by Kai Wucherpfennig, director of Dana-Farber’s Center for Cancer Immunotherapy Research, and Biostats professor, Shirley Liu, identified the immunotherapy resistance mechanism in melanoma cells.
Both research groups converged on a discovery that resistance to immune checkpoint blockade is critically controlled by changes in a group of proteins, called a chromatin remodeling complex, that regulate how DNA is packaged in cells. The components of this complex, known as SWI/SNF, open up stretches of tightly wound DNA so that it can be read by the cell in order to activate certain genes to make proteins. According to the authors of the second study, the protein products of certain genes in the PBAF complex “represent targets for immunotherapy, because inactivating mutations sensitize tumor cells to T-cell mediated attack.” In the future, finding ways to alter target molecules may prove to be a crucial method for extending the benefit of immunotherapy to larger patient populations.