@article{ca4b27ccdda44e08ae5cf79ff6b614fa,
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.",
author = "Xiaoxiao Ma and Nadeem Riaz and Samstein, {Robert M.} and Mark Lee and Vladimir Makarov and Cristina Valero and Diego Chowell and Fengshen Kuo and Douglas Hoen and Fitzgerald, {Conall W.R.} and Hui Jiang and Jonathan Alektiar and Alban, {Tyler J.} and Ivan Juric and Parthasarathy, {Prerana Bangalore} and Yu Zhao and Sabio, {Erich Y.} and Richa Verma and Srivastava, {Raghvendra M.} and Lynda Vuong and Wei Yang and Xiao Zhang and Jingming Wang and Chu, {Lawrence K.} and Wang, {Stephen L.} and Kelly, {Daniel W.} and Xin Pei and Jiapeng Chen and Rona Yaeger and Dmitriy Zamarin and Ahmet Zehir and Mithat G{\"o}nen and Morris, {Luc G.T.} and Chan, {Timothy A.}",
note = "Funding Information: T.A.C. is a cofounder of Gritstone Oncology and holds equity. T.A.C. holds equity in An2H. T.A.C. acknowledges grant funding from Bristol-Myers Squibb, AstraZeneca, Illumina, Pfizer, An2H and Eisai. T.A.C. has served as an advisor for Bristol-Myers, MedImmune, Squibb, Illumina, Eisai, AstraZeneca and An2H. T.A.C., L.G.T.M., R.M.S. and D.C. are inventors on intellectual property held by MSKCC on using tumor mutation burden to predict immunotherapy response, with pending patent, which has been licensed to PGDx. C.V. acknowledges research grant funding from Fundaci{\'o}n Alfonso Mart{\'i}n Escudero. D.Z. received consulting fees from Agenus, Hookipa Biotech, Targovax, AstraZeneca, Synthekine, Mana Therapeutics, Xencor, Crown Biosciences and Memgen. D.Z. receives grant/research support from AstraZeneca, Roche and Plexxikon. D.Z. holds stock options for Immunos Therapeutics, Calidi Biotherapeutics, Mana Therapeutics and Accurius. D.Z. has a patent related to use of Newcastle Disease Virus for cancer therapy with royalties paid from Merck. R.Y. has served as an advisor for Natera, Array BioPharma/Pfizer and Mirati Therapeutics and has received research support to her institution from Array BioPharma/Pfizer, Boehringer Ingelheim and Mirati Therapeutics. The remaining authors declare no competing interests. Funding Information: We thank colleagues at the Cleveland Clinic flow core, Cleveland Clinic genomics core, Center for Immunotherapy and Precision-Immuno-Oncology Shared Platforms, MSK core facilities (including Integrated Genomics Operation (IGO), Flow Cytometry Core Facility (FCCF) and Molecular Cytology Core Facility (MCCF)) for processing our samples and providing important suggestions. We thank colleagues at the Molecular Diagnostics Service in the Department of Pathology, and the Marie-Josee and Henry R. Kravis Center for Molecular Oncology Marie-Jos{\'e}e of MSK for establishing and generating the MSK-IMPACT data. We thank all the members and alumni of the Chan laboratory at MSK and CCF, as well as the LRI of CCF and HOPP of MSK for their generous help and support of this study. The results presented here are based in part on data generated or collected by the TCGA Research Network, Broad CCLE, ICGC. We acknowledge funding sources including National Institutes of Health (NIH) R01 CA205426 (T.A.C.), NIH R35 CA232097 (T.A.C.), the STARR Cancer Consortium (T.A.C.), NIH DP5 OD028171 (R.M.S), the Burroughs Wellcome Fund (R.M.S.) and the NIH/National Cancer Institute Cancer Center Support Grant P30 CA008748 (MSKCC). Funding Information: We thank colleagues at the Cleveland Clinic flow core, Cleveland Clinic genomics core, Center for Immunotherapy and Precision-Immuno-Oncology Shared Platforms, MSK core facilities (including Integrated Genomics Operation (IGO), Flow Cytometry Core Facility (FCCF) and Molecular Cytology Core Facility (MCCF)) for processing our samples and providing important suggestions. We thank colleagues at the Molecular Diagnostics Service in the Department of Pathology, and the Marie-Josee and Henry R. Kravis Center for Molecular Oncology Marie-Jos{\'e}e of MSK for establishing and generating the MSK-IMPACT data. We thank all the members and alumni of the Chan laboratory at MSK and CCF, as well as the LRI of CCF and HOPP of MSK for their generous help and support of this study. The results presented here are based in part on data generated or collected by the TCGA Research Network, Broad CCLE, ICGC. We acknowledge funding sources including National Institutes of Health (NIH) R01 CA205426 (T.A.C.), NIH R35 CA232097 (T.A.C.), the STARR Cancer Consortium (T.A.C.), NIH DP5 OD028171 (R.M.S), the Burroughs Wellcome Fund (R.M.S.) and the NIH/National Cancer Institute Cancer Center Support Grant P30 CA008748 (MSKCC). Publisher Copyright: {\textcopyright} 2022, The Author(s), under exclusive licence to Springer Nature America, Inc.",
year = "2022",
month = jul,
doi = "10.1038/s41588-022-01108-w",
language = "English",
volume = "54",
pages = "996--1012",
journal = "Nature Genetics",
issn = "1061-4036",
publisher = "Nature Publishing Group",
number = "7",
}