2026-05-08 ラトガース大学
＜関連情報＞
- https://www.rutgers.edu/news/why-cell-therapy-cancer-treatment-sometimes-fails
- https://www.cell.com/cell-reports/fulltext/S2211-1247(25)01567-0
加齢に伴うCD8+ T細胞の老化を制御する、年齢非依存的かつ標的可能な転写因子ネットワーク Age-independent and targetable transcription factor networks regulating CD8+ T cell senescence in aging humans
Paolo S. Turano ∙ Elizabeth Akbulut ∙ Hannah K. Dewald ∙ … ∙ Patricia Fitzgerald-Bocarsly ∙ Utz Herbig ∙ Ricardo Iván Martínez-Zamudio
Cell Reports Published:January 6, 2026
DOI:https://doi.org/10.1016/j.celrep.2025.116795
Graphical abstract
Highlights
- Aging humans accumulate senescent CD8+ T cells across all differentiation states
- Age-insensitive transcription factor networks control the transition to senescence
- Targeting the senescence TF networks partially restores response to TCR stimulation
- CD8+ T cell senescence gene signatures predict the response to CAR-T cell therapy
Summary
The age-related decline in immunity is accompanied by the accumulation of senescent CD8+ T cells. Using senescent cell isolation coupled with multi-omics profiling, we reveal the transition to senescence to be controlled by chromatin state-specific transcription factor (TF) networks in younger and older donors independent of age. These TF networks mediate widespread enhancer remodeling, repressing cell identity genes while upregulating inflammatory and secretory pathways. Inhibition or downregulation of AP1, KLF5, or RUNX2 modulates the transcriptional output and partially restores the blunted response to stimulation of senescent CD8+ T cells. Senescent CD8+ T cell gene signatures also predict responsiveness to chimeric antigen receptor (CAR)-T cell therapy in diffuse large B cell lymphomas. Overall, our study defines the gene-regulatory mechanisms underlying human CD8+ T cell senescence, highlights TF network perturbation as a viable strategy to manipulate the senescence state, and identifies senescent CD8+ T cell gene signatures as prognostic tools for immunotherapy outcome.
