Περίληψη:
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).
Συγγραφείς:
Liu, D.
Schilling, B.
Liu, D.
Sucker, A.
Livingstone, E.
Jerby-Amon, L.
Zimmer, L.
Gutzmer, R.
Satzger, I.
Loquai, C.
Grabbe, S.
Vokes, N.
Margolis, C.A.
Conway, J.
He, M.X.
Elmarakeby, H.
Dietlein, F.
Miao, D.
Tracy, A.
Gogas, H.
Goldinger, S.M.
Utikal, J.
Blank, C.U.
Rauschenberg, R.
von Bubnoff, D.
Krackhardt, A.
Weide, B.
Haferkamp, S.
Kiecker, F.
Izar, B.
Garraway, L.
Regev, A.
Flaherty, K.
Paschen, A.
Van Allen, E.M.
Schadendorf, D.
Λέξεις-κλειδιά:
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
