Transcriptomic profiling reveals distinct subsets of immune checkpoint inhibitor induced myositis

Author:

Pinal-Fernandez IagoORCID,Quintana AngelaORCID,Milisenda Jose Cesar,Casal-Dominguez Maria,Muñoz-Braceras Sandra,Derfoul Assia,Torres-Ruiz Jiram,Pak Katherine,Dell'Orso Stefania,Naz Faiza,Gutierrez-Cruz Gustavo,Milone Margherita,Shelly Shahar,Duque-Jaimez Yaiza,Tobias-Baraja Ester,Matas-Garcia Ana,Garrabou Gloria,Padrosa Joan,Ros Javier,Trallero-Araguás Ernesto,Walitt Brian,Christopher-Stine Lisa,Lloyd Thomas E,Zhao Chen,Swift Shannon,Rajan Arun,Grau-Junyent Josep Maria,Selva-O'Callaghan AlbertORCID,Liewluck Teerin,Mammen Andrew LeeORCID

Abstract

ObjectivesInflammatory myopathy or myositis is a heterogeneous family of immune-mediated diseases including dermatomyositis (DM), antisynthetase syndrome (AS), immune-mediated necrotising myopathy (IMNM) and inclusion body myositis (IBM). Immune checkpoint inhibitors (ICIs) can also cause myositis (ICI-myositis). This study was designed to define gene expression patterns in muscle biopsies from patients with ICI-myositis.MethodsBulk RNA sequencing was performed on 200 muscle biopsies (35 ICI-myositis, 44 DM, 18 AS, 54 IMNM, 16 IBM and 33 normal muscle biopsies) and single nuclei RNA sequencing was performed on 22 muscle biopsies (seven ICI-myositis, four DM, three AS, six IMNM and two IBM).ResultsUnsupervised clustering defined three distinct transcriptomic subsets of ICI-myositis: ICI-DM, ICI-MYO1 and ICI-MYO2. ICI-DM included patients with DM and anti-TIF1γ autoantibodies who, like DM patients, overexpressed type 1 interferon-inducible genes. ICI-MYO1 patients had highly inflammatory muscle biopsies and included all patients that developed coexisting myocarditis. ICI-MYO2 was composed of patients with predominant necrotising pathology and low levels of muscle inflammation. The type 2 interferon pathway was activated both in ICI-DM and ICI-MYO1. Unlike the other types of myositis, all three subsets of ICI-myositis patients overexpressed genes involved in the IL6 pathway.ConclusionsWe identified three distinct types of ICI-myositis based on transcriptomic analyses. The IL6 pathway was overexpressed in all groups, the type I interferon pathway activation was specific for ICI-DM, the type 2 IFN pathway was overexpressed in both ICI-DM and ICI-MYO1 and only ICI-MYO1 patients developed myocarditis.

Publisher

BMJ

Subject

General Biochemistry, Genetics and Molecular Biology,Immunology,Immunology and Allergy,Rheumatology

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