eIF2α as a Target to Prevent T Cell Stress and Loss of Function in Cancer Immunotherapy
Researchers here identify eIF2α as a target for interventions that prevent T cells from shutting down after prolonged activity in a tumor environment. The stress response to extended activity is normally protective, but in this case it prevents T cells from being as effective as they might be, which contributes to an established tumor's compromise of the immune system. This sort of approach offers the promise of improving cancer immunotherapies, increasing the damage that each T cell can do to tumor tissue.
The stress response in T cells can lead to their inability to curtail tumor growth. Researchers found that T cells exposed to the environment of solid cancers undergo a natural response to stress that shuts off their function, limiting T cell ability to kill tumors. By manipulating multiple proteins in the stress response pathway inside T cells, the team showed that it was possible to overcome the intrinsic T cell stress response to allow the immune system to thwart cancer growth.
At the center of this research is a protein called PKR ER-like kinase (PERK), which is a major stress sensor for all cell types, including T cells, but has not been deeply studied in the context of immunity. That is, when a T cell is under duress - like when faced with the hostile environment created by cancer cells - it is PERK that responds to the stress in a way that causes cells to stop secreting proteins in an effort to help the cell survive.
Researchers found that when PERK is activated, modification of one molecule called phosphorylated eIF2-alpha is responsible for the T cell momentarily stopping protein synthesis during the stress response. When researchers forced phosphorylated eIF2-alpha to cease its natural function, the T cells continued protein synthesis, and T cells were able to continue to control tumor growth in mice. This research shows that it is very possible to tweak T cells genetically or pharmacologically to enhance their ability to battle cancer tumor cells.
Link: https://news.unchealthcare.org/2022/12/why-dont-t-cells-destroy-solid-tumors-during-immunotherapy/