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 outcom...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-09-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-40959-7 |
| _version_ | 1827709907470647296 |
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| author | 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 Leonid A. Pobezinsky |
| author_facet | 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 Leonid A. Pobezinsky |
| author_sort | Alexandria C. Wells |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-10T17:30:48Z |
| format | Article |
| id | doaj.art-91894239e4cb479a9f76d823674243ce |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-10T17:30:48Z |
| publishDate | 2023-09-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-91894239e4cb479a9f76d823674243ce2023-11-20T10:02:48ZengNature PortfolioNature Communications2041-17232023-09-0114111510.1038/s41467-023-40959-7Let-7 enhances murine anti-tumor CD8 T cell responses by promoting memory and antagonizing terminal differentiationAlexandria C. Wells0Kaito A. Hioki1Constance C. Angelou2Adam C. Lynch3Xueting Liang4Daniel J. Ryan5Iris Thesmar6Saule Zhanybekova7Saulius Zuklys8Jacob Ullom9Agnes Cheong10Jesse Mager11Georg A. Hollander12Elena L. Pobezinskaya13Leonid A. Pobezinsky14Department of Veterinary and Animal science, University of MassachusettsDepartment of Veterinary and Animal science, University of MassachusettsDepartment of Veterinary and Animal science, University of MassachusettsDepartment of Veterinary and Animal science, University of MassachusettsDepartment of Veterinary and Animal science, University of MassachusettsDepartment of Veterinary and Animal science, University of MassachusettsDepartment of Veterinary and Animal science, University of MassachusettsPediatric Immunology, Department of Biomedicine, University of Basel and University Children’s Hospital BaselPediatric Immunology, Department of Biomedicine, University of Basel and University Children’s Hospital BaselDepartment of Veterinary and Animal science, University of MassachusettsDepartment of Veterinary and Animal science, University of MassachusettsDepartment of Veterinary and Animal science, University of MassachusettsPediatric Immunology, Department of Biomedicine, University of Basel and University Children’s Hospital BaselDepartment of Veterinary and Animal science, University of MassachusettsDepartment of Veterinary and Animal science, University of MassachusettsAbstract 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.https://doi.org/10.1038/s41467-023-40959-7 |
| spellingShingle | 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 Leonid A. Pobezinsky Let-7 enhances murine anti-tumor CD8 T cell responses by promoting memory and antagonizing terminal differentiation Nature Communications |
| title | Let-7 enhances murine anti-tumor CD8 T cell responses by promoting memory and antagonizing terminal differentiation |
| title_full | Let-7 enhances murine anti-tumor CD8 T cell responses by promoting memory and antagonizing terminal differentiation |
| title_fullStr | Let-7 enhances murine anti-tumor CD8 T cell responses by promoting memory and antagonizing terminal differentiation |
| title_full_unstemmed | Let-7 enhances murine anti-tumor CD8 T cell responses by promoting memory and antagonizing terminal differentiation |
| title_short | Let-7 enhances murine anti-tumor CD8 T cell responses by promoting memory and antagonizing terminal differentiation |
| title_sort | let 7 enhances murine anti tumor cd8 t cell responses by promoting memory and antagonizing terminal differentiation |
| url | https://doi.org/10.1038/s41467-023-40959-7 |
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