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Supplementary Data from PD-1 Blockade in Solid Tumors with Defects in Polymerase Epsilon

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posted on 2023-04-04, 00:01 authored by Benoit Rousseau, Ivan Bieche, Eric Pasmant, Nadim Hamzaoui, Nicolas Leulliot, Lucas Michon, Aurelien de Reynies, Valerie Attignon, Michael B. Foote, Julien Masliah-Planchon, Magali Svrcek, Romain Cohen, Victor Simmet, Paule Augereau, David Malka, Antoine Hollebecque, Damien Pouessel, Carlos Gomez-Roca, Rosine Guimbaud, Amandine Bruyas, Marielle Guillet, Jean-Jacques Grob, Muriel Duluc, Sophie Cousin, Christelle de la Fouchardiere, Aude Flechon, Frederic Rolland, Sandrine Hiret, Esma Saada-Bouzid, Olivier Bouche, Thierry Andre, Diane Pannier, Farid El Hajbi, Stephane Oudard, Christophe Tournigand, Jean-Charles Soria, Stephane Champiat, Drew G. Gerber, Dennis Stephens, Michelle F. Lamendola-Essel, Steven B. Maron, Bill H. Diplas, Guillem Argiles, Asha R. Krishnan, Severine Tabone-Eglinger, Anthony Ferrari, Neil H. Segal, Andrea Cercek, Natalie Hoog-Labouret, Frederic Legrand, Clotilde Simon, Assia Lamrani-Ghaouti, Luis A. Diaz, Pierre Saintigny, Sylvie Chevret, Aurelien Marabelle
Supplementary Data from PD-1 Blockade in Solid Tumors with Defects in Polymerase Epsilon

Funding

Centre de Ressources Biologiques du Centre Léon Bérard

Marie-Josée and Henry R. Kravis Center for Molecular Oncology

NCI Cancer Center Core

NIH

Integrated Cancer Research Site LYriCAN

PLASCAN

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ARTICLE ABSTRACT

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 rate to anti–PD-1 monotherapy. This study illustrates how specific DNA repair defects sensitize to immunotherapy. POLE proofreading deficiency represents a novel agnostic biomarker for response to PD-1 checkpoint blockade therapy. POLE proofreading deficiency leads to high tumor mutational burden with high tumor-infiltrating lymphocytes and predicts anti–PD-1 efficacy in mismatch repair–proficient tumors. Conversely, tumors harboring POLE mutations not affecting proofreading derived no benefit from PD-1 blockade. POLE proofreading deficiency is a new tissue-agnostic biomarker for cancer immunotherapy.See related video: https://vimeo.com/720727355This article is highlighted in the In This Issue feature, p. 1397

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