Microtubule-Driven Stress Granule Dynamics Regulate Inhibitory Immune Checkpoint Expression in T Cells.
Fiche publication
Date publication
janvier 2019
Journal
Cell reports
Auteurs
Membres identifiés du Cancéropôle Est :
Dr ROSSI Cédric
Tous les auteurs :
Franchini DM, Lanvin O, Tosolini M, Patras de Campaigno E, Cammas A, Péricart S, Scarlata CM, Lebras M, Rossi C, Ligat L, Pont F, Arimondo PB, Laurent C, Ayyoub M, Despas F, Lapeyre-Mestre M, Millevoi S, Fournié JJ
Lien Pubmed
Résumé
Despite the clinical success of blocking inhibitory immune checkpoint receptors such as programmed cell death-1 (PD-1) in cancer, the mechanisms controlling the expression of these receptors have not been fully elucidated. Here, we identify a post-transcriptional mechanism regulating PD-1 expression in T cells. Upon activation, the PDCD1 mRNA and ribonucleoprotein complexes coalesce into stress granules that require microtubules and the kinesin 1 molecular motor to proceed to translation. Hence, PD-1 expression is highly sensitive to microtubule or stress granule inhibitors targeting this pathway. Evidence from healthy donors and cancer patients reveals a common regulation for the translation of CTLA4, LAG3, TIM3, TIGIT, and BTLA but not of the stimulatory co-receptors OX40, GITR, and 4-1BB mRNAs. In patients, disproportionality analysis of immune-related adverse events for currently used microtubule drugs unveils a significantly higher risk of autoimmunity. Our findings reveal a fundamental mechanism of immunoregulation with great importance in cancer immunotherapy.
Mots clés
PD-1, T cells, immune checkpoints, kinesin, mRNA, microtubules, stress granules
Référence
Cell Rep. 2019 01 2;26(1):94-107.e7