 |
 |
GEO help: Mouse over screen elements for information. |
|
| Status |
Public on Aug 02, 2023 |
| Title |
Let-7 enhances murine anti-tumor CD8 T cell responses by promoting memory and antagonizing terminal differentiation |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
|
| Summary |
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 microRNAs 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 may suggest a strategy in developing next-generation immunotherapies by preserving the multipotency of effector cells rather than enhancing the efficacy of differentiation.
|
| |
|
| Overall design |
Comparative gene expression profiling analysis of RNA-seq data for T cells (naïve, activated, or CTLs) on either a WT, Lin28b transgenic, or Let-7 transgenic background (n=3 for each sample group).
|
| |
|
| Contributor(s) |
Wells AC, Hioki KA, Angelou CC, Pobezinskaya EL, Pobezinsky LA |
| Citation(s) |
37696797 |
| NIH grant(s) |
| Grant ID |
Grant title |
Affiliation |
Name |
| R01 AI146188 |
Defining post-transcriptional mechanisms that control CD8 T cell longevity, proliferation and differentiation |
University of Massachusetts-Amherst |
Leonid Pobezinskiy |
| R21 AI133041 |
Defining the role of let-7 miRNAs in the differentiation of exhausted and memory T cells |
University of Massachusetts-Amherst |
Leonid Pobezinskiy |
|
| |
| Submission date |
May 15, 2023 |
| Last update date |
Sep 21, 2023 |
| Contact name |
Leonid Pobezinsky |
| E-mail(s) |
lpobezinsky@umass.edu
|
| Organization name |
University of Massachusetts Amherst
|
| Department |
Veterinary and Animal Sciences
|
| Street address |
661 N Pleasant St
|
| City |
Amherst |
| State/province |
MA |
| ZIP/Postal code |
01003 |
| Country |
USA |
| |
|
| Platforms (1) |
|
| Samples (27)
|
| GSM7349987 |
Lin28bTg, Naïve, 1 |
| GSM7349988 |
Lin28bTg, Naïve, 2 |
| GSM7349989 |
Lin28bTg, Naïve, 3 |
| GSM7349990 |
Let-7Tg, Naïve, 1 |
| GSM7349991 |
Let-7Tg, Naïve, 2 |
| GSM7349992 |
Let-7Tg, Naïve, 3 |
| GSM7349993 |
WT, 12 Hours activated, 1 |
| GSM7349994 |
WT, 12 Hours activated, 2 |
| GSM7349995 |
WT, 12 Hours activated, 3 |
| GSM7349996 |
Lin28bTg, 12 Hours activated, 1 |
| GSM7349997 |
Lin28bTg, 12 Hours activated, 2 |
| GSM7349998 |
Lin28bTg, 12 Hours activated, 3 |
| GSM7349999 |
Let-7Tg, 12 Hours activated, 1 |
| GSM7350000 |
Let-7Tg, 12 Hours activated, 2 |
| GSM7350001 |
Let-7Tg, 12 Hours activated, 3 |
| GSM7350002 |
WT, 5 Days activated, 1 |
| GSM7350003 |
WT, 5 Days activated, 2 |
| GSM7350004 |
WT, 5 Days activated, 3 |
| GSM7350005 |
Lin28bTg, 5 Days activated, 1 |
| GSM7350006 |
Lin28bTg, 5 Days activated, 2 |
| GSM7350007 |
Lin28bTg, 5 Days activated, 3 |
| GSM7350008 |
Let-7Tg, 5 Days activated, 1 |
| GSM7350009 |
Let-7Tg, 5 Days activated, 2 |
| GSM7350010 |
Let-7Tg, 5 Days activated, 3 |
|
| Relations |
| BioProject |
PRJNA972698 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE232541_summary_0h.csv.gz |
3.2 Mb |
(ftp)(http) |
CSV |
| GSE232541_summary_12h.csv.gz |
3.0 Mb |
(ftp)(http) |
CSV |
| GSE232541_summary_5d.csv.gz |
3.1 Mb |
(ftp)(http) |
CSV |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
|
|
|
|
 |
Less...
More...