γδ T cells are well suited to fighting cancer owing to an ability to detect stressed cells through T cell receptors that are generally not restricted to antigen-presenting molecules, unlike αβ T cell receptors. This mechanism of general stress sensing can potentially enable the detection and lysis of a more diverse range of tumors. Data published in Nature now show the molecular complexity of this stress-sensing ability specifically in human Vγ9Vδ2 T cells — a T cell subset known for its ability to kill cancer cells — which recognize the butyrophilin complex proteins BTN2A1 and BTN3A, the latter requiring activation by phosphoantigen metabolites produced by tumor cells. The researchers conducted a genome-wide CRISPR screen to identify genes that regulate the killing of cancer cells by human Vγ9Vδ2 T cells, and measured gene signature scores from 33 cancer types in The Cancer Genome Atlas. A second screen was used to identify regulators of BTN3A surface expression in cancer cells. Among several altered metabolic programs, the researchers noted that suppressing ATP production by oxidative phosphorylation or glycolysis induced cancer-cell expression of BTN3A. Subsequent functional analyses showed that the energy sensor AMPK is crucial for this ATP crisis to be translated into increased expression of the cell surface butyrophilin complex, and a small-molecule AMPK agonist was used to boost complex expression and subsequent γδ T cell killing in vitro. These findings paint a complex picture of the interactions between γδ T cells and cancer cells and highlight AMPK as an important stress response regulator that controls the identification of cancer cells for termination by Vγ9Vδ2 T cells. Whether these findings can be used to design or boost γδ T cell immunotherapies is an intriguing question for future studies.
Original reference: Nature 621, 188–195 (2023)
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