VIB-KU Leuven Center for Cancer Biology lambrechtslab

ICI

Single-cell transcriptomics identifies pathogenic T-helper 17.1 cells and pro-inflammatory monocytes in immune checkpoint inhibitor-related pneumonitis

ICI
  • 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. 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 TBX21 and RORC, IFN-G, IL-17A, CSF2, and cytotoxicity genes. Type 1 regulatory T cells and naïve-like CD4+ T cells were also enriched. Within the CD8+ T-cell compartment, mainly effector memory T cells were increased. Correspondingly, myeloid cells in ICI-pneumonitis bronchoalveolar lavage fluid were relatively depleted of anti-inflammatory resident alveolar macrophages while pro-inflammatory ‘M1-like’ monocytes were enriched compared with control samples. Importantly, a feedforward loop, in which GM-CSF production by pathogenic T-helper 17.1 cells promotes tissue inflammation and IL-23 production by pro-inflammatory monocytes and vice versa, has been well characterized in multiple autoimmune disorders but has never been identified in ICI-related pneumonitis. This finding yields several novel potential therapeutic targets for the treatment of ICI-pneumonitis.
  • Please note following minor corrigendum to the manuscript, regarding the total number of cells analyzed: “After quality control and filtering, we obtained 118,017 cells of which 66,852 were derived from ICI-pneumonitis BALF and 51,165 from demographically-matched control BALF."
  • Single-cell transcriptomics identifies pathogenic T-helper 17.1 cells and pro-inflammatory monocytes in immune checkpoint inhibitor-related pneumonitis - Franken et al. - 2022 - J IMMUNOTHER CANCER

Data Availability

  • Raw sequencing reads of all single-cell experiments (scRNA-seq, scTCR-seq) have been deposited in the European Genome-phenome Archive (EGA) under study no. EGAS00001006762 and with data accession no. EGAD00001009723. Requests for accessing raw sequencing reads will have to be reviewed by the UZLeuven-VIB data access committee. Any data shared will only be released prior to a Data Transfer Agreement that will have to include the necessary conditions to guarantee protection of personal data (according to European GDPR law). 
  • Alternatively, a download of the read count data is more readily available from this website. In addition to the read counts, meta-data regarding diagnosis (ICI-pneumonitis versus controls) have been added to the files. To comply with GDPR regulations, please note that individual sample identifiers used for this data deposit (alphabetical ID) are different from and cannot be traced back to the patient identifiers used throughout the manuscript (numerical ID).

Data files