Single-cell transcriptomics identifies pathogenic T-helper 17.1 cells and pro-inflammatory monocytes in immune checkpoint inhibitor-related pneumonitis.
Anti-Inflammatory Agents
Apoptosis Regulatory Proteins
Granulocyte-Macrophage Colony-Stimulating Factor
Humans
Immune Checkpoint Inhibitors
/ adverse effects
Interleukin-17
Interleukin-6
Monocytes
Nuclear Receptor Subfamily 1, Group F, Member 3
Pneumonia
RNA
Receptors, Granulocyte-Macrophage Colony-Stimulating Factor
Transcriptome
Autoimmunity
Computational Biology
Immunotherapy
Lung Neoplasms
Programmed Cell Death 1 Receptor
Journal
Journal for immunotherapy of cancer
ISSN: 2051-1426
Titre abrégé: J Immunother Cancer
Pays: England
ID NLM: 101620585
Informations de publication
Date de publication:
09 2022
09 2022
Historique:
accepted:
13
09
2022
entrez:
28
9
2022
pubmed:
29
9
2022
medline:
1
10
2022
Statut:
ppublish
Résumé
Immune checkpoint inhibitor (ICI)-related pneumonitis is the most frequent fatal immune-related adverse event associated with programmed cell death protein-1/programmed death ligand-1 blockade. The pathophysiology however remains largely unknown, owing to limited and contradictory findings in existing literature pointing at either T-helper 1 or T-helper 17-mediated autoimmunity. In this study, we aimed to gain novel insights into the mechanisms of ICI-related pneumonitis, thereby identifying potential therapeutic targets. In this prospective observational study, single-cell RNA and T-cell receptor sequencing was performed on bronchoalveolar lavage fluid of 11 patients with ICI-related pneumonitis and 6 demographically-matched patients with cancer without ICI-related pneumonitis. Single-cell transcriptomic immunophenotyping and cell fate mapping coupled to T-cell receptor repertoire analyses were performed. We observed enrichment of both CD4+ and CD8+ T cells in ICI-pneumonitis bronchoalveolar lavage fluid. The CD4+ T-cell compartment showed an increase of pathogenic T-helper 17.1 cells, characterized by high co-expression of Using single-cell transcriptomics, we identified accumulation of pathogenic T-helper 17.1 cells in ICI-pneumonitis bronchoalveolar lavage fluid-a phenotype explaining previous divergent findings on T-helper 1 versus T-helper 17 involvement in ICI-pneumonitis-,putatively engaging in detrimental crosstalk with pro-inflammatory 'M1-like' monocytes. This finding yields several novel potential therapeutic targets for the treatment of ICI-pneumonitis. Most notably repurposing anti-IL-23 merits further research as a potential efficacious and safe treatment for ICI-pneumonitis.
Sections du résumé
BACKGROUND
Immune checkpoint inhibitor (ICI)-related pneumonitis is the most frequent fatal immune-related adverse event associated with programmed cell death protein-1/programmed death ligand-1 blockade. The pathophysiology however remains largely unknown, owing to limited and contradictory findings in existing literature pointing at either T-helper 1 or T-helper 17-mediated autoimmunity. In this study, we aimed to gain novel insights into the mechanisms of ICI-related pneumonitis, thereby identifying potential therapeutic targets.
METHODS
In this prospective observational study, single-cell RNA and T-cell receptor sequencing was performed on bronchoalveolar lavage fluid of 11 patients with ICI-related pneumonitis and 6 demographically-matched patients with cancer without ICI-related pneumonitis. Single-cell transcriptomic immunophenotyping and cell fate mapping coupled to T-cell receptor repertoire analyses were performed.
RESULTS
We observed enrichment of both CD4+ and CD8+ T cells in ICI-pneumonitis bronchoalveolar lavage fluid. The CD4+ T-cell compartment showed an increase of pathogenic T-helper 17.1 cells, characterized by high co-expression of
CONCLUSIONS
Using single-cell transcriptomics, we identified accumulation of pathogenic T-helper 17.1 cells in ICI-pneumonitis bronchoalveolar lavage fluid-a phenotype explaining previous divergent findings on T-helper 1 versus T-helper 17 involvement in ICI-pneumonitis-,putatively engaging in detrimental crosstalk with pro-inflammatory 'M1-like' monocytes. This finding yields several novel potential therapeutic targets for the treatment of ICI-pneumonitis. Most notably repurposing anti-IL-23 merits further research as a potential efficacious and safe treatment for ICI-pneumonitis.
Identifiants
pubmed: 36171010
pii: jitc-2022-005323
doi: 10.1136/jitc-2022-005323
pmc: PMC9528720
pii:
doi:
Substances chimiques
Anti-Inflammatory Agents
0
Apoptosis Regulatory Proteins
0
Immune Checkpoint Inhibitors
0
Interleukin-17
0
Interleukin-6
0
Nuclear Receptor Subfamily 1, Group F, Member 3
0
Receptors, Granulocyte-Macrophage Colony-Stimulating Factor
0
RNA
63231-63-0
Granulocyte-Macrophage Colony-Stimulating Factor
83869-56-1
Types de publication
Journal Article
Observational Study
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.
Déclaration de conflit d'intérêts
Competing interests: None declared.
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