John Gordon, Co-Founder, Director, VP Scientific Affairs at Celentyx Ltd, shared on LinkedIn:
“MAJOR RETHINK in Breaking Study at BioRxiv – Reinvigoration of Translational Activity in Dysfunctional T cells Initiates the Early Intratumoral Response to PD1 Immune Checkpoint Blockade.
T cells are key effectors of antitumor responses elicited by PD-1 blockade. However, it remains elusive by which mechanism(s) PD-1 blockade initiates T cell-driven antitumor immunity in cancer tissues.
Here, Paulien Kaptein, Nadine Slingerland, Anne van der Leun, et al (with corresponding author Daniela Thommen) dissect early T cell reactivation upon anti-PD-1 in patient-derived tumor fragments. Using bispecific antibodies to target anti-PD-1 to individual T cell subsets, they demonstrate that intratumoral CD8+ and CD4+ T cells can independently drive immune remodeling of the tumor microenvironment.
The CD8+ and CD4+ T cells that respond to anti-PD-1 exhibit a shared dysfunctional gene program, characterized by tumor-reactivity, terminal exhaustion, effector capacity, and reduced translational activity.
Notably, rather than acting through transcriptional rewiring, anti-PD-1 reinvigorates dysfunctional T cells by overcoming this translational barrier, resulting in restored effector function.
Altogether, these results reveal dysfunctional T cells as initiators of early tissue responses to PD-1 blockade and identify a novel mode of their therapeutic reinvigoration through restoration of translational control.
FIGURE | Upper: Schematic overview of mechanism of action of αPD-1, leading to T cell reinvigoration, and proposed mechanism of action of αCD8xαPD1 and αCD4xαPD1, leading to specific T cell inhibition | Lower: Capacity of both CD8+ and CD4+ T cells to induce TME remodeling following PD-1 blockade (Schematic overview of experimental strategy).”
Title: Reinvigoration of translational activity in dysfunctional T cells initiates the early intratumoral response to PD-1 blockade
Authors: Paulien Kaptein, Nadine Slingerland, Anne M. van der Leun, Eline Runderkamp, Roos A. Wagensveld, S. Michael Chin, Janniek R. Mors, Mercedes Machuca-Ostos, Timm Reissig, Kelly D. Moynihan, Ivana M. Djuretic, Yik A. Yeung, Ton N.M. Schumacher, Daniela S. Thommen
Read The Full Article at bioRxiv.
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