{"doi":"10.1038/s41591-019-0654-5","title":"Integrative molecular and clinical modeling of clinical outcomes to PD1 blockade in patients with metastatic melanoma","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.","journal":"Nature Medicine","year":2019,"id":2363,"datarank":1.0082138551185966,"base_score":6.721425700790643,"endowment":6.721425700790643,"self_citation_contribution":1.0082138551185966,"citation_network_contribution":0.0,"self_endowment_contribution":1.0082138551185966,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":829,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.0839,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2019-12-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":5597,"name":"Bastian Schilling","orcid":"0000-0001-8859-4103","position":1,"is_corresponding":false},{"id":28944,"name":"Derek Liu","orcid":"0000-0001-5744-1147","position":2,"is_corresponding":false},{"id":28945,"name":"Antje Sucker","orcid":"0000-0002-2753-9626","position":3,"is_corresponding":false},{"id":28946,"name":"Elisabeth Livingstone","orcid":"0000-0001-8279-9239","position":4,"is_corresponding":false},{"id":5594,"name":"Livnat Jerby-Arnon","orcid":"0000-0002-4037-386X","position":5,"is_corresponding":false},{"id":28947,"name":"Lisa Zimmer","orcid":"0000-0002-3680-3521","position":6,"is_corresponding":false},{"id":28948,"name":"Ralf Gutzmer","orcid":"0000-0001-7921-2820","position":7,"is_corresponding":false},{"id":28949,"name":"Imke Satzger","orcid":"0000-0001-5983-2125","position":8,"is_corresponding":false},{"id":28950,"name":"Carmen Loquai","orcid":null,"position":9,"is_corresponding":false},{"id":28951,"name":"Stephan Grabbe","orcid":"0000-0002-6863-8719","position":10,"is_corresponding":false},{"id":28952,"name":"Claire A. 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