@article{b452f271a0dc45538603151932898068,
title = "Immune selection determines tumor antigenicity and influences response to checkpoint inhibitors",
abstract = "In cancer, evolutionary forces select for clones that evade the immune system. Here we analyzed >10,000 primary tumors and 356 immune-checkpoint-treated metastases using immune dN/dS, the ratio of nonsynonymous to synonymous mutations in the immunopeptidome, to measure immune selection in cohorts and individuals. We classified tumors as immune edited when antigenic mutations were removed by negative selection and immune escaped when antigenicity was covered up by aberrant immune modulation. Only in immune-edited tumors was immune predation linked to CD8 T cell infiltration. Immune-escaped metastases experienced the best response to immunotherapy, whereas immune-edited patients did not benefit, suggesting a preexisting resistance mechanism. Similarly, in a longitudinal cohort, nivolumab treatment removes neoantigens exclusively in the immunopeptidome of nonimmune-edited patients, the group with the best overall survival response. Our work uses dN/dS to differentiate between immune-edited and immune-escaped tumors, measuring potential antigenicity and ultimately helping predict response to treatment.",
author = "Luis Zapata and Giulio Caravagna and Williams, {Marc J.} and Eszter Lakatos and Khalid AbdulJabbar and Benjamin Werner and Diego Chowell and Chela James and Lucie Gourmet and Salvatore Milite and Ahmet Acar and Nadeem Riaz and Chan, {Timothy A.} and Graham, {Trevor A.} and Andrea Sottoriva",
note = "Funding Information: L.Z. is supported by the European Union{\textquoteright}s Horizon 2020 research and innovation program under the Marie Sk{\l}odowska-Curie Research Fellowship scheme (846614). A.S. and T.A.G. are supported by the Wellcome Trust (202778/B/16/Z and 202778/Z/16/Z, respectively) and Cancer Research UK (A22909 to A.S., A19771 and DRCNPG-May21_100001 to T.A.G.). We acknowledge funding from the National Institute of Health (National Cancer Institute grant U54 CA217376) to A.S. and T.A.G. This work was also supported by a Wellcome Trust award to the Centre for Evolution and Cancer (105104/Z/14/Z) and by a AIRC/CRUK/FC Accelerator Award to A.S. (CRUK: A26815, AIRC: 2279). We thank M. Punta and C.-A. Garin for support and discussion. We thank S. Quesada and E. Ghorani for important insights on the project. This publication and the underlying study have been made possible partly on the basis of the data that Hartwig Medical Foundation and the Center of Personalised Cancer Treatment have made available to the study. Figures 1 and 5a were created with Biorender.com. G.C. acknowledges funding from AIRC under MFAG 2020-ID. 24913 project—P.I. Caravagna Giulio. Funding Information: L.Z. is supported by the European Union{\textquoteright}s Horizon 2020 research and innovation program under the Marie Sk{\l}odowska-Curie Research Fellowship scheme (846614). A.S. and T.A.G. are supported by the Wellcome Trust (202778/B/16/Z and 202778/Z/16/Z, respectively) and Cancer Research UK (A22909 to A.S., A19771 and DRCNPG-May21_100001 to T.A.G.). We acknowledge funding from the National Institute of Health (National Cancer Institute grant U54 CA217376) to A.S. and T.A.G. This work was also supported by a Wellcome Trust award to the Centre for Evolution and Cancer (105104/Z/14/Z) and by a AIRC/CRUK/FC Accelerator Award to A.S. (CRUK: A26815, AIRC: 2279). We thank M. Punta and C.-A. Garin for support and discussion. We thank S. Quesada and E. Ghorani for important insights on the project. This publication and the underlying study have been made possible partly on the basis of the data that Hartwig Medical Foundation and the Center of Personalised Cancer Treatment have made available to the study. Figures and were created with Biorender.com. G.C. acknowledges funding from AIRC under MFAG 2020-ID. 24913 project—P.I. Caravagna Giulio. Publisher Copyright: {\textcopyright} 2023, The Author(s).",
year = "2023",
month = mar,
doi = "10.1038/s41588-023-01313-1",
language = "English",
volume = "55",
pages = "451--460",
journal = "Nature Genetics",
issn = "1061-4036",
publisher = "Nature Publishing Group",
number = "3",
}