Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
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.
Source : Open Agenda
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