Functional landscapes of POLE and POLD1 mutations in checkpoint blockade-dependent antitumor immunity Journal Article
| Authors: | Ma, X.; Riaz, N.; Samstein, R. M.; Lee, M.; Makarov, V.; Valero, C.; Chowell, D.; Kuo, F.; Hoen, D.; Fitzgerald, C. W. R.; Jiang, H.; Alektiar, J.; Alban, T. J.; Juric, I.; Parthasarathy, P. B.; Zhao, Y.; Sabio, E. Y.; Verma, R.; Srivastava, R. M.; Vuong, L.; Yang, W.; Zhang, X.; Wang, J.; Chu, L. K.; Wang, S. L.; Kelly, D. W.; Pei, X.; Chen, J.; Yaeger, R.; Zamarin, D.; Zehir, A.; Gönen, M.; Morris, L. G. T.; Chan, T. A. |
| Article Title: | Functional landscapes of POLE and POLD1 mutations in checkpoint blockade-dependent antitumor immunity |
| 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. © 2022, The Author(s), under exclusive licence to Springer Nature America, Inc. |
| Keywords: | genetics; mutation; neoplasm; neoplasms; mouse; animal; animals; mice; immunotherapy; dna directed dna polymerase alpha; dna directed dna polymerase gamma; dna polymerase iii; dna polymerase ii; humans; human; poly adp ribose binding protein; poly-adp-ribose binding proteins; pold1 protein, human |
| Journal Title: | Nature Genetics |
| Volume: | 54 |
| Issue: | 7 |
| ISSN: | 1061-4036 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2022-07-01 |
| Start Page: | 996 |
| End Page: | 1012 |
| Language: | English |
| DOI: | 10.1038/s41588-022-01108-w |
| PUBMED: | 35817971 |
| PROVIDER: | scopus |
| PMCID: | PMC10181095 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 August 2022 -- Source: Scopus |
Altmetric
Citation Impact
BMJ Impact Analytics
MSK Authors
Related MSK Work