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Ma, Xiaoxiao; Riaz, Nadeem; Samstein, Robert M; Lee, Mark; Makarov, Vladimir; Valero, Cristina; Chowell, Diego; Kuo, Fengshen; Hoen, Douglas; Fitzgerald, Conall W R; Jiang, Hui; Alektiar, Jonathan; Alban, Tyler J; Juric, Ivan; Parthasarathy, Prerana Bangalore; Zhao, Yu; Sabio, Erich Y; Verma, Richa; Srivastava, Raghvendra M; Vuong, Lynda; Yang, Wei; Zhang, Xiao; Wang, Jingming; Chu, Lawrence K; Wang, Stephen L; Kelly, Daniel W; Pei, Xin; Chen, Jiapeng; Yaeger, Rona; Zamarin, Dmitriy; Zehir, Ahmet; Gönen, Mithat; Morris, Luc G T; Chan, Timothy A
Nature genetics, 07/2022, Volume: 54, Issue: 7Journal Article
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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