AUTHOR=Janelle Valérie , Neault Mathieu , Lebel Marie-Ève , De Sousa Dave Maurice , Boulet Salix , Durrieu Ludovic , Carli Cédric , Muzac Chloé , Lemieux Sébastien , Labrecque Nathalie , Melichar Heather J. , Mallette Frédérick A. , Delisle Jean-Sébastien TITLE=p16INK4a Regulates Cellular Senescence in PD-1-Expressing Human T Cells JOURNAL=Frontiers in Immunology VOLUME=12 YEAR=2021 URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2021.698565 DOI=10.3389/fimmu.2021.698565 ISSN=1664-3224 ABSTRACT=

T-cell dysfunction arising upon repeated antigen exposure prevents effective immunity and immunotherapy. Using various clinically and physiologically relevant systems, we show that a prominent feature of PD-1-expressing exhausted T cells is the development of cellular senescence features both in vivo and ex vivo. This is associated with p16INK4a expression and an impaired cell cycle G1 to S-phase transition in repeatedly stimulated T cells. We show that these T cells accumulate DNA damage and activate the p38MAPK signaling pathway, which preferentially leads to p16INK4a upregulation. However, in highly dysfunctional T cells, p38MAPK inhibition does not restore functionality despite attenuating senescence features. In contrast, p16INK4a targeting can improve T-cell functionality in exhausted CAR T cells. Collectively, this work provides insights into the development of T-cell dysfunction and identifies T-cell senescence as a potential target in immunotherapy.