GeneEditing in T cell Leukemia to Promote Immunomodulatory Forms of Cell Death
Cell death removes damaged, pre-cancerous and infected cells. The study of cell death has yielded significant insight into the formation and maintenance of leukemia cells. Many types of cell death exist, but only one form known as apoptosis has been extensively investigated in the context of leukemia. Chemotherapeutics can activate apoptotic cell death but many leukemias continue to be resistant to apoptosis and cannot be eradicated by current chemotherapeutics. In particular, the generation of effective immune responses against leukemia cells remains a significant challenge contributing to relapse of leukemia.
One exciting possibility for cancer biology is that the induction of alternative forms of cell death, including a form of death known as necroptosis, can drive immune responses directed against leukemia cells. This type of cell death works by punching holes in the cell causing the cell to rupture and release molecules that can drive immune responses against molecules found only in leukemia cells. In contrast, apoptosis results in the packaging of cell contents to avoid activation of immune responses and tumor immunity. During infection, necroptosis can be beneficial for exposing pathogens that reside inside cells, thereby activating immune responses.
We are now developing drug combinations and genetic editing tools to remove the key molecular brakes on necroptosis to enable leukemia cells to engage this explosive type of cell death. We predict that this will lead to life-long immune responses against the molecules found only in leukemia cells.