Jean-Christophe Beltra
Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
Uncovering exhausted CD8 T cell developmental biology reveals opportunities to improve cancer immunotherapy
Exhaustion of CD8 T-cells prevents optimal control of chronic viral infections and cancer. This hypofunctional state of CD8 T-cell differentiation is also a major barrier to current anti-cancer immunotherapies. Overcoming this process is key to achieve better therapeutic benefits but has proven challenging due to the epigenetic stability of this program. During my postdoc, I identified a new subset of exhausted CD8 T-cell (TEX intermediate [TEXint]) that mediates the benefits of PD-1 therapy and re-acquires partial effector biology despite an exhaustion landscape. This work pointed-out flexibility in the epigenetic program of exhaustion at the point of TEXint cell formation. I identified the transcription factor Stat5a was a major drive of TEXint cell development. Manipulating the Stat5a axis in TEX strongly synergized with PD-1 blockade and rewired TEX towards a more durably protective state with superior anti-tumor potential. This work provided first evidence for the therapeutic reprogramming of TEX cells and underlined the relevance of exploring TEXint-related pathways for better therapeutic manipulation of TEX cells.
Selected references
- Beltra, J.-C. et al. Enhanced STAT5a activation rewires exhausted CD8 T cells during chronic stimulation to acquire a hybrid durable effector like state. bioRxiv 2022.2010.2003.509766, doi:10.1101/2022.10.03.509766 (2022)
- Beltra, J. C. et al. Developmental relationships of four exhausted CD8(+) T cell subsets reveals underlying transcriptional and epigenetic landscape control mechanisms. Immunity 52, 825-841 (2020)
- Abdel-Hakeem, M. S. et al. Epigenetic scarring of exhausted T cells hinders memory differentiation upon eliminating chronic antigenic stimulation. Nat Immunol 22, 1008-1019, doi:10.1038/s41590-021-00975-5 (2021)