Journal article
Let-7 enhances murine anti-tumor CD8 T cell responses by promoting memory and antagonizing terminal differentiation
- 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.
- Publication status:
- Published
- Peer review status:
- Peer reviewed
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(Preview, Version of record, pdf, 2.6MB, Terms of use)
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- Publisher copy:
- 10.1038/s41467-023-40959-7
Authors
+ National Institutes of Health
More from this funder
- Funder identifier:
- https://ror.org/01cwqze88
- Grant:
- R01 AI146188
- Publisher:
- Springer Nature
- Journal:
- Nature Communications More from this journal
- Volume:
- 14
- Issue:
- 1
- Article number:
- 5585
- Publication date:
- 2023-09-11
- Acceptance date:
- 2023-08-17
- DOI:
- EISSN:
-
2041-1723
- Pmid:
-
37696797
- Language:
-
English
- Keywords:
- Pubs id:
-
1528693
- Local pid:
-
pubs:1528693
- Deposit date:
-
2024-09-24
Terms of use
- Copyright holder:
- Wells et al.
- Copyright date:
- 2023
- Rights statement:
- Copyright © 2023, The Author(s). This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
- Licence:
- CC Attribution (CC BY)
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