PD-1 blockade in solid tumors with defects in polymerase epsilon.
Fiche publication
Date publication
avril 2022
Journal
Cancer discovery
Auteurs
Membres identifiés du Cancéropôle Est :
Pr BOUCHE Olivier
Tous les auteurs :
Rousseau B, Bieche I, Pasmant E, Hamzaoui N, Leulliot N, Michon L, de Reynies A, Attignon V, Foote MB, Masliah-Planchon J, Svrcek M, Cohen R, Simmet V, Augereau P, Malka D, Hollebecque A, Pouessel D, Gomez-Roca C, Guimbaud R, Bruyas A, Guillet M, Grob JJ, Duluc M, Cousin S, de la Fouchardiere C, Flechon A, Rolland F, Hiret S, Saada-Bouzid E, Bouche O, Andre T, Pannier D, El Hajbi F, Oudard S, Tournigand C, Soria JC, Champiat S, Gerber DG, Stephens D, Lamendola-Essel MF, Maron SB, Diplas BH, Argiles G, Krishnan AR, Tabone-Eglinger S, Ferrari A, Segal NH, Cercek A, Hoog-Labouret N, Legrand F, Simon C, Lamrani-Ghaouti A, Diaz LA, Saintigny P, Chevret S, Marabelle A
Lien Pubmed
Résumé
Missense mutations in the polymerase epsilon (POLE) gene have been reported to generate proofreading defects resulting in an ultramutated genome and sensitize tumors to checkpoint blockade immunotherapy. However, many POLE mutated tumors do not respond to such treatment. To better understand the link between POLE mutation variants and response to immunotherapy, we. prospectively assessed the efficacy of nivolumab in a multicenter clinical trial in patients bearing advanced mismatch repair proficient POLE-mutated solid tumors. We found that only tumors harboring selective POLE pathogenic mutations in the DNA binding or catalytic site of the exonuclease domain presented high mutational burden with specific single base substitution signature, high T-cell infiltrates, and high response rate to anti-PD1 monotherapy. This study illustrates how specific DNA repair defects can sensitize to immunotherapy, POLE proofreading deficiency representing a novel tumor agnostic biomarker for response to PD-1 checkpoint blockade therapy.
Référence
Cancer Discov. 2022 Apr 10;: