biostudies-literatureRousseau BCentre de Ressources Biologiques du Centre Léon BérardMarie-Josée and Henry R. Kravis Center for Molecular Oncology NCI Cancer Center CoreIntegrated Cancer Research Site LYriCANNCI NIH HHSNIHPLASCAN1435-1448https://www.ebi.ac.uk/biostudies/studies/S-EPMC9167784biostudies-literatureUnknown12(6)Missense mutations in the polymerase epsilon (POLE) gene have been reported to generate proofreading defects resulting in an ultramutated genome and to 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 a specific single-base substitution signature, high T-cell infiltrates, and a high response rCancer discoveryPD-1 Blockade in Solid Tumors with Defects in Polymerase Epsilon.PMC9167784T32-CA009512INCa-DGOS-Inserm_12563T32 CA009512P30 CA008748P30-CA008748#BB-0033-0005017-CONV-0002Gomez-Roca CPouessel DLamrani-Ghaouti Ade la Fouchardiere CBouche OSvrcek MOudard SStephens DLamendola-Essel MFCercek AHoog-Labouret NSegal NHKrishnan ARRousseau BGuimbaud RChampiat SSimmet VLegrand FMarabelle ADiplas BHPasmant ECousin SGrob JJArgiles Gde Reynies AHollebecque AAndre TGerber DGRolland FTabone-Eglinger SPannier DGuillet MFlechon ABieche IFerrari ADiaz LAChevret SSoria JCMalka DTournigand CFoote MBLeulliot NEl Hajbi FMasliah-Planchon JDuluc MCohen RAttignon VAugereau PMichon LHiret SSaada-Bouzid EHamzaoui NSaintigny PBruyas AMaron SBSimon CfalsePD-1 Blockade in Solid Tumors with Defects in Polymerase Epsilon.Missense mutations in the polymerase epsilon (POLE) gene have been reported to generate proofreading defects resulting in an ultramutated genome and to 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 a specific single-base substitution signature, high T-cell infiltrates, and a high response r2022-01-01T00:00:00Z2022 Jun2026-05-09T19:30:18.169Z2025-04-19T22:50:01.19ZS-EPMC91677843539888010.1158/2159-8290.CD-21-052110.1158/2159-8290.cd-21-0521