Functional landscapes of POLE and POLD1 mutations in checkpoint blockade-dependent antitumor immunity

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

Research output: Contribution to journalArticlepeer-review

29 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)996-1012
Number of pages17
JournalNature Genetics
Volume54
Issue number7
DOIs
StatePublished - Jul 2022

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