PD-1 Blockade in Solid Tumors with Defects in Polymerase Epsilon

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 BruyasMarielle 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

Research output: Contribution to journalArticlepeer-review

27 Scopus citations

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.

Original languageEnglish
Pages (from-to)1435-1448
Number of pages14
JournalCancer Discovery
Volume12
Issue number6
DOIs
StatePublished - 2 Jun 2022
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2022 The Authors; Published by the American Association for Cancer Research.

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