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Ref Type Journal Article
PMID (35817971)
Authors Ma X, Riaz N, Samstein RM, Lee M, Makarov V, Valero C, Chowell D, Kuo F, Hoen D, Fitzgerald CWR, Jiang H, Alektiar J, Alban TJ, Juric I, Parthasarathy PB, Zhao Y, Sabio EY, Verma R, Srivastava RM, Vuong L, Yang W, Zhang X, Wang J, Chu LK, Wang SL, Kelly DW, Pei X, Chen J, Yaeger R, Zamarin D, Zehir A, Gönen M, Morris LGT, Chan TA
Title Functional landscapes of POLE and POLD1 mutations in checkpoint blockade-dependent antitumor immunity.
Journal Vol Issue Date Pages Journal Short Title
Nature genetics 54 7 2022 Jul 996-1012 Nat Genet
URL
Abstract Text Defects in pathways governing genomic fidelity have been linked to improved response to immune checkpoint blockade therapy (ICB). Pathogenic POLE/POLD1 mutations can cause hypermutation, yet how diverse mutations in POLE/POLD1 influence antitumor immunity following ICB is unclear. Here, we comprehensively determined the effect of POLE/POLD1 mutations in ICB and elucidated the mechanistic impact of these mutations on tumor immunity. Murine syngeneic tumors harboring Pole/Pold1 functional mutations displayed enhanced antitumor immunity and were sensitive to ICB. Patients with POLE/POLD1 mutated tumors harboring telltale mutational signatures respond better to ICB than patients harboring wild-type or signature-negative tumors. A mutant POLE/D1 function-associated signature-based model outperformed several traditional approaches for identifying POLE/POLD1 mutated patients that benefit from ICB. Strikingly, the spectrum of mutational signatures correlates with the biochemical features of neoantigens. Alterations that cause POLE/POLD1 function-associated signatures generate T cell receptor (TCR)-contact residues with increased hydrophobicity, potentially facilitating T cell recognition. Altogether, the functional landscapes of POLE/POLD1 mutations shape immunotherapy efficacy.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References