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

• Published in: Nature communications Vol. 14; no. 1; pp. 5585 - 15
• Main Authors: 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., Pobezinsky, Leonid A.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 11.09.2023; Nature Publishing Group; Nature Portfolio
• Subjects: 1-Phosphatidylinositol 3-kinase; 13; 13/106; 13/109; 13/31; 13/95; 38; 38/39; 38/91; 631/250/1619/554/1834; 631/250/2152/1566/2493; 631/250/2502/2055; 631/250/580/1884; 64; 64/60; AKT protein; Animal models; CD8 antigen; Cell activation; Cell death; Cell differentiation; Cell fate; Differentiation; Effector cells; Humanities and Social Sciences; Immune checkpoint inhibitors; Immune clearance; Immune response; Immune response (cell-mediated); Immune system; Immunological memory; Immunotherapy; In vivo methods and tests; Lymphocytes; Lymphocytes T; Maintenance; Memory cells; Metabolism; multidisciplinary; Reactive oxygen species; Science; Science (multidisciplinary); Signal transduction; TOR protein; Tumors
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-023-40959-7

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. Effective CD8 + T cell immunity requires the generation of a long-lived memory pool and the maintenance of a non-exhausted effector T cell pool. The implementation of immune checkpoint blockade can reduced levels of exhaustion but lacks the ability to support memory formation in the effector pool. Here the authors suggest a role for Let-7 in the enhancement of the anti-tumor CD8 + T cell response by supporting memory via modulation of metabolic and differentiation state.