Let-7 enhances murine anti-tumor CD8 T cell responses by promoting memory and antagonizing terminal differentiation

Alexandria C. Wells, Kaito A. Hioki, Constance C. Angelou, Adam C. Lynch, Xueting Liang, Daniel J. Ryan, Iris Thesmar, Saule Zhanybekova, Saulius Zuklys, Jacob Ullom, Agnes Cheong, Jesse Mager, Georg A. Hollander, Elena L. Pobezinskaya () and Leonid A. Pobezinsky ()
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Alexandria C. Wells: University of Massachusetts
Kaito A. Hioki: University of Massachusetts
Constance C. Angelou: University of Massachusetts
Adam C. Lynch: University of Massachusetts
Xueting Liang: University of Massachusetts
Daniel J. Ryan: University of Massachusetts
Iris Thesmar: University of Massachusetts
Saule Zhanybekova: University of Basel and University Children’s Hospital Basel
Saulius Zuklys: University of Basel and University Children’s Hospital Basel
Jacob Ullom: University of Massachusetts
Agnes Cheong: University of Massachusetts
Jesse Mager: University of Massachusetts
Georg A. Hollander: University of Basel and University Children’s Hospital Basel
Elena L. Pobezinskaya: University of Massachusetts
Leonid A. Pobezinsky: University of Massachusetts

Nature Communications, 2023, vol. 14, issue 1, 1-15

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-40959-7

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