Transcriptomic profiling reveals distinct subsets of immune checkpoint inhibitor induced myositis

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.

Senescent fibro-adipogenic progenitors are potential drivers of pathology in inclusion body myositis

“…2 a, b). Cell types were assigned according to the expression of canonical markers (a full list of all marker genes is given in Supplemental File 1) based on previous transcriptomic studies of skeletal muscle [ 9 , 30 , 50 , 52 ]. While non-myogenic cells were separated based on their transcriptomic profiles, the classification of myogenic cells was more challenging.…”

Highly multiplexed spatial analysis identifies tissue-resident memory T cells as drivers of ulcerative and immune checkpoint inhibitor induced colitis

“…16 Involvement of the IL-23/IL-17 axis has been demonstrated in various irAEs and is more pronounced after cICI. 30,45,46 Paradoxically, direct IL-17 blocking, e.g. with secukinumab, has been shown to induce intestinal inflammation.…”

Highly multiplexed spatial analysis identifies tissue-resident memory T cells as drivers of ulcerative and immune checkpoint inhibitor colitis

“… 16 Involvement of the IL-23/IL-17 axis has been demonstrated in various irAEs and is more pronounced after cICI. 30 , 45 , 46 Paradoxically, direct IL-17 blocking, e.g., with secukinumab, has been shown to induce intestinal inflammation. 47 Pro-homeostatic IL-17 production is independent of IL-23, 48 and therefore more upstream interventions directed against IL-23, such as ustekinumab, or the IL-6 receptor inhibitor tocilizumab might hold promise.…”