Researchers co-led by Ludwig Harvard’s Constantine Mitsiades explored the genetic determinants and mechanisms of cancer cell susceptibility and resistance to natural killer (NK) cell targeting using single-cell and genome-scale functional genomics screens of interacting NK and blood cancer cells. They also profiled the sensitivity of multiple blood cancer cell lines to NK cell targeting and evaluated mechanisms of sensitivity to NK killing and escape from such targeting via CRISPR gene editing screens. By integrating these data and patient genomic profiles, Constantine and his colleagues generated a comprehensive portrait of functionally validated molecular mechanisms that influence how NK cells recognize and kill malignant hematopoietic cells, and how those cells escape targeting. They reported in a December paper in Immunity that the interaction of NK and cancer cells activates the former and induces in both transcriptional states—including interferon-related gene expression—that depend on the type and molecular features of the cancer cell. The study identified a panoply of genes regulating sensitivity and resistance to NK cell killing, including adhesion-related glycoproteins, protein fucosylation genes and transcriptional regulators. The publicly available data, which include gene targets that induce susceptibility to NK cell killing, hold clues to the design of novel immunotherapies.
Single-cell functional genomics reveals determinants of sensitivity and resistance to natural killer cells in blood cancers
Immunity, 2023 December 12