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JCI Insight. 2018 Apr 5;3(7). pii: 98575. doi: 10.1172/jci.insight.98575. eCollection 2018 Apr 5.

Comprehensive immunoproteogenomic analyses of malignant pleural mesothelioma.

Author information

1
Division of Thoracic Surgery, Michael E. DeBakey Department of Surgery.
2
Department of Biochemistry and Molecular Biology.
3
Section of Hematology-Oncology, Department of Medicine.
4
Department of Radiology, and.
5
Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas, USA.
6
Department of Systems Biology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
7
Division of Abdominal Transplantation, Immune Evaluation Laboratory, Michael E. DeBakey Department of Surgery, and.
8
Department of Medicine, Baylor College of Medicine, Houston, Texas, USA.
9
Center for Translational Research in Inflammatory Diseases, Michael E. DeBakey VA Medical Center, Houston, Texas, USA.

Abstract

We generated a comprehensive atlas of the immunologic cellular networks within human malignant pleural mesothelioma (MPM) using mass cytometry. Data-driven analyses of these high-resolution single-cell data identified 2 distinct immunologic subtypes of MPM with vastly different cellular composition, activation states, and immunologic function; mass spectrometry demonstrated differential abundance of MHC-I and -II neopeptides directly identified between these subtypes. The clinical relevance of this immunologic subtyping was investigated with a discriminatory molecular signature derived through comparison of the proteomes and transcriptomes of these 2 immunologic MPM subtypes. This molecular signature, representative of a favorable intratumoral cell network, was independently associated with improved survival in MPM and predicted response to immune checkpoint inhibitors in patients with MPM and melanoma. These data additionally suggest a potentially novel mechanism of response to checkpoint blockade: requirement for high measured abundance of neopeptides in the presence of high expression of MHC proteins specific for these neopeptides.

KEYWORDS:

Cancer immunotherapy; Expression profiling; Immunology; Oncology; Proteomics

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