title: Integrated analysis of somatic mutations and immune microenvironment in malignant pleural mesothelioma.
abstract: To investigate the link between the genomic landscape of cancer cells and immune microenvironment in tumor tissues, we characterized somatic mutations and tumor-infiltrating lymphocytes (TILs) in malignant pleural mesothelioma (MPM), including mutation/neoantigen load, spatial heterogeneity of somatic mutations of cancer cells and TILs (T-cell receptor β (TCRβ) repertoire), and expression profiles of immune-related genes using specimens of three different tumor sites (anterior, posterior, and diaphragm) obtained from six MPM patients. Integrated analysis identified the distinct patterns of somatic mutations and the immune microenvironment signatures both intratumorally and interindividually. MPM cases showed intratumoral heterogeneity in somatic mutations with unique TCRβ clonotypes of TILs that were restricted to each tumor site, suggesting the presence of a neoantigen-related immune response. Correlation analyses showed that higher neoantigen load was significantly correlated with stronger clonal expansion of TILs (p= 0.048) and a higher expression level of an immune-associated cytolytic factor (PRF1(p= 0.0041) in tumor tissues), suggesting that high neoantigen loads in tumor cells might promote expansion of functional tumor-specific T cells in the tumor bed. Our results collectively indicate that MPM tumors constitute a diverse heterogeneity in both the genomic landscape and immune microenvironment, and that mutation/neoantigen load may affect the immune microenvironment in MPM tissues.
authors.affiliation: Department of Medicine, The University of Chicago , Chicago, IL, USA.
authors.forename: Kazuma
authors.initials: K
authors.lastname: Kiyotani
authors.affiliation: Department of Medicine, The University of Chicago , Chicago, IL, USA.
authors.forename: Jae-Hyun
authors.initials: JH
authors.lastname: Park
authors.affiliation: Department of Medicine, The University of Chicago , Chicago, IL, USA.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Inoue
authors.affiliation: Department of Pathology, The University of Chicago , Chicago, IL, USA.
authors.forename: Aliya
authors.initials: A
authors.lastname: Husain
authors.affiliation: Department of Medicine, The University of Chicago , Chicago, IL, USA.
authors.forename: Sope
authors.initials: S
authors.lastname: Olugbile
authors.affiliation: Department of Medicine, The University of Chicago , Chicago, IL, USA.
authors.forename: Makda
authors.initials: M
authors.lastname: Zewde
authors.affiliation: Department of Medicine, The University of Chicago, Chicago, IL, USA; Department of Surgery, The University of Chicago, Chicago, IL, USA.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Nakamura
authors.affiliation: Department of Surgery, The University of Chicago, Chicago, IL, USA; Department of Thoracic and Cardiovascular Surgery, Loyola University Medical Center, Maywood, IL, USA.
authors.forename: Wickii T
authors.initials: WT
authors.lastname: Vigneswaran
keywords: Heterogeneity; T-cell receptor; malignant pleural mesothelioma; neoantigen; tumor-infiltrating lymphocytes; whole-exome sequencing