@article{3077365,
    title = "Integrative molecular and clinical modeling of clinical outcomes to PD1 blockade in patients with metastatic melanoma",
    author = "Liu, D. and Schilling, B. and Liu, D. and Sucker, A. and Livingstone, E. and Jerby-Amon, L. and Zimmer, L. and Gutzmer, R. and Satzger, I. and Loquai, C. and Grabbe, S. and Vokes, N. and Margolis, C.A. and Conway, J. and He, M.X. and Elmarakeby, H. and Dietlein, F. and Miao, D. and Tracy, A. and Gogas, H. and Goldinger, S.M. and Utikal, J. and Blank, C.U. and Rauschenberg, R. and von Bubnoff, D. and Krackhardt, A. and Weide, B. and Haferkamp, S. and Kiecker, F. and Izar, B. and Garraway, L. and Regev, A. and Flaherty, K. and Paschen, A. and Van Allen, E.M. and Schadendorf, D.",
    journal = "Journal of Natural Medicines",
    year = "2019",
    volume = "25",
    number = "12",
    pages = "1916-1927",
    publisher = "Lithuanian Nature Research Centre",
    issn = "1861-0293",
    doi = "10.1038/s41591-019-0654-5",
    keywords = "ipilimumab;  major histocompatibility antigen class 1;  major histocompatibility antigen class 2;  nivolumab;  pembrolizumab;  programmed death 1 receptor;  CTLA4 protein, human;  cytotoxic T lymphocyte antigen 4;  monoclonal antibody;  nivolumab;  PDCD1 protein, human;  pembrolizumab;  programmed death 1 receptor;  transcriptome, advanced cancer;  antigen presentation;  Article;  cancer immunotherapy;  cancer patient;  clinical outcome;  cohort analysis;  drug resistance;  female;  gene mutation;  genomics;  human;  human tissue;  major clinical study;  male;  metastatic melanoma;  overall survival;  patient history of therapy;  priority journal;  progression free survival;  RNA sequence;  transcriptomics;  treatment response;  whole exome sequencing;  genetics;  immunology;  melanoma;  metastasis;  mutation;  pathology, Antibodies, Monoclonal, Humanized;  Antigen Presentation;  CTLA-4 Antigen;  Drug Resistance, Neoplasm;  Female;  Humans;  Male;  Melanoma;  Mutation;  Neoplasm Metastasis;  Nivolumab;  Programmed Cell Death 1 Receptor;  Transcriptome;  Whole Exome Sequencing",
    abstract = "Immune-checkpoint blockade (ICB) has demonstrated efficacy in many tumor types, but predictors of responsiveness to anti-PD1 ICB are incompletely characterized. In this study, we analyzed a clinically annotated cohort of patients with melanoma (n = 144) treated with anti-PD1 ICB, with whole-exome and whole-transcriptome sequencing of pre-treatment tumors. We found that tumor mutational burden as a predictor of response was confounded by melanoma subtype, whereas multiple novel genomic and transcriptomic features predicted selective response, including features associated with MHC-I and MHC-II antigen presentation. Furthermore, previous anti-CTLA4 ICB exposure was associated with different predictors of response compared to tumors that were naive to ICB, suggesting selective immune effects of previous exposure to anti-CTLA4 ICB. Finally, we developed parsimonious models integrating clinical, genomic and transcriptomic features to predict intrinsic resistance to anti-PD1 ICB in individual tumors, with validation in smaller independent cohorts limited by the availability of comprehensive data. Broadly, we present a framework to discover predictive features and build models of ICB therapeutic response. © 2019, The Author(s)."
}