Publication Date
2023
Journal or Book Title
Nature Communications
Abstract
The success of the CD8 T cell-mediated immune response against infections and tumors depends on the formation of a long-lived memory pool, and the protection of effector cells from exhaustion. The advent of checkpoint blockade therapy has significantly improved anti-tumor therapeutic outcomes by reversing CD8 T cell exhaustion, but fails to generate effector cells with memory potential. Here, using in vivo mouse models, we show that let-7 miRNAs determine CD8 T cell fate, where maintenance of let-7 expression during early cell activation results in memory CD8 T cell formation and tumor clearance. Conversely, let-7-deficiency promotes the generation of a terminal effector population that becomes vulnerable to exhaustion and cell death in immunosuppressive environments and fails to reject tumors. Mechanistically, let-7 restrains metabolic changes that occur during T cell activation through the inhibition of the PI3K/AKT/mTOR signaling pathway and production of reactive oxygen species, potent drivers of terminal differentiation and exhaustion. Thus, our results reveal a role for let-7 in the time-sensitive support of memory formation and the protection of effector cells from exhaustion. Overall, our data suggest a strategy in developing next-generation immunotherapies by preserving the multipotency of effector cells rather than enhancing the efficacy of differentiation.
DOI
https://doi.org/10.1038/s41467-023-40959-7
Volume
14
License
UMass Amherst Open Access Policy
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.
Recommended Citation
Wells, Alexandria C.; Hioki, Kaito A.; Angelou, Constance C.; Lynch, Adam C.; Liang, Xueting; Ryan, Daniel J.; Thesmar, Iris; Zhanybekova, Saule; Zuklys, Saulius; Ullom, Jacob; Cheong, Agnes; Mager, Jesse; Hollander, Georg A.; Pobezinskaya, Elena L.; and Pobezinsky, Leonid A., "Let-7 enhances murine anti-tumor CD8 T cell responses by promoting memory and antagonizing terminal differentiation" (2023). Nature Communications. 23.
https://doi.org/10.1038/s41467-023-40959-7