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p16INK4a Regulates Cellular Senescence in PD-1-Expressing Human T Cells.

Janelle V, Neault M, Lebel ME, De Sousa DM, Boulet S, Durrieu L, Carli C, Muzac C, Lemieux S, Labrecque N, Melichar HJ, Mallette FA, Delisle JS

Research Centre, Hôpital Maisonneuve-Rosemont, Montreal, QC, Canada.

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.

Front Immunol 2021;12:698565.

Pubmed ID: 34434190

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