Integrative molecular and clinical modeling of clinical outcomes to PD1 blockade in patients with metastatic melanoma.,Nature Medicine

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Integrative molecular and clinical modeling of clinical outcomes to PD1 blockade in patients with metastatic melanoma.
Nature Medicine ( IF 58.7 ) Pub Date : 2019-12-02 , DOI: 10.1038/s41591-019-0654-5
David Liu _{1,

2} , Bastian Schilling _{3,

4,

5} , Derek Liu _{1,

2,

6} , Antje Sucker _{4,

5} , Elisabeth Livingstone _{4,

5} , Livnat Jerby-Arnon ₂ , Lisa Zimmer _{4,

5} , Ralf Gutzmer ₇ , Imke Satzger ₇ , Carmen Loquai ₈ , Stephan Grabbe ₈ , Natalie Vokes _{1,

2} , Claire A Margolis _{1,

2} , Jake Conway _{2,

6} , Meng Xiao He _{2,

6,

9} , Haitham Elmarakeby _{1,

2} , Felix Dietlein _{1,

2} , Diana Miao _{1,

2,

6} , Adam Tracy ₂ , Helen Gogas ₁₀ , Simone M Goldinger ₁₁ , Jochen Utikal _{12,

13} , Christian U Blank ₁₄ , Ricarda Rauschenberg _{15,

16,

17} , Dagmar von Bubnoff ₁₈ , Angela Krackhardt _{5,

19} , Benjamin Weide ₂₀ , Sebastian Haferkamp ₂₁ , Felix Kiecker ₂₂ , Ben Izar _{1,

2} , Levi Garraway ₂₃ , Aviv Regev ₂ , Keith Flaherty ₂₄ , Annette Paschen _{4,

5} , Eliezer M Van Allen _{1,

2} , Dirk Schadendorf _{4,

5}

Affiliation

Dana-Farber Cancer Institute, Boston, MA, USA.
Broad Institute of Harvard and MIT, Cambridge, MA, USA.
Department of Dermatology, University Hospital Würzburg, Würzburg, Germany.
Department of Dermatology, University Hospital, Essen, Germany.
German Cancer Consortium of Translational Cancer Research, German Cancer Research Center, Heidelberg, Germany.
Harvard Medical School, Boston, MA, USA.
Skin Cancer Center Hannover, Department of Dermatology and Allergy, Hannover Medical School, Hannover, Germany.
Department of Dermatology, University Medical Center, Mainz, Germany.
Biophysics Program, Harvard University, Cambridge, MA, USA.
First Department of Medicine, National and Kapodistrian University of Athens, Athens, Greece.
Department of Dermatology, University Hospital Zürich, Zürich, Switzerland.
Department of Dermatology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, Mannheim, Germany.
Skin Cancer Unit, German Cancer Research Center, Heidelberg, Germany.
Department of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
Skin Cancer Center at the University Cancer Centre, Department of Dermatology, Faculty of Medicine, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
National Center for Tumor Diseases, Dresden, Germany.
German Cancer Research Centre, Heidelberg, Germany.
Department of Dermatology, Medical Center- University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
Medizinische Klinik III, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany.
Department of Dermatology, University Medical Center Tübingen, Tübingen, Germany.
Department of Dermatology, University Hospital Regensburg, Regensburg, Germany.
Department of Dermatology, University Hospital Berlin, Berlin, Germany.
Eli Lilly and Co., Indianapolis, IN, USA.
Massachusetts General Hospital, Boston, MA, USA.

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.

中文翻译：

转移性黑色素瘤患者 PD1 阻断临床结果的综合分子和临床模型。

免疫检查点阻断 (ICB) 已在许多肿瘤类型中证明有效，但对抗 PD1 ICB 反应性的预测因子尚未完全表征。在这项研究中，我们分析了一组经过临床注释的黑色素瘤患者（n = 144），他们接受了抗 PD1 ICB 治疗，并对治疗前的肿瘤进行了全外显子组和全转录组测序。我们发现作为反应预测因子的肿瘤突变负荷被黑色素瘤亚型混淆，而多个新的基因组和转录组学特征预测选择性反应，包括与 MHC-I 和 MHC-II 抗原呈递相关的特征。此外，与未接触过 ICB 的肿瘤相比，先前的抗 CTLA4 ICB 暴露与不同的反应预测因子相关，这表明先前暴露于抗 CTLA4 ICB 的选择性免疫效应。最后，我们开发了整合临床、基因组和转录组学特征的简约模型，以预测个体肿瘤对抗 PD1 ICB 的内在耐药性，并在较小的独立队列中进行验证，但受限于综合数据的可用性。概括地说，我们提出了一个框架来发现预测特征和建立 ICB 治疗反应的模型。

更新日期：2019-12-02

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