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Differential effects of tofacitinib on macrophage activation contribute to lack of response in ulcerative colitis patients

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Dataset overview

Participants 11
Samples 23
Reuse readiness 7.4/10 evidence-backed score

Differential effects of tofacitinib on macrophage activation contribute to lack of response in ulcerative colitis patients.

Melón-Ardanaz E, Veny M, Corraliza AM, Gudiño V, Garrido-Trigo A, Sanzo-Machuca Á, Buendia M, Esteller M, et al. · Journal of Crohn's & colitis · 2025

Abstract

<h4>Background and aims</h4>Tofacitinib, a Janus kinase inhibitor, is approved for the treatment of moderate-to-severe ulcerative colitis. Nonetheless, 40-60% of patients will not respond adequately. The mechanisms underlying responses to tofacitinib remain unknown.<h4>Methods</h4>We applied single-cell and/or bulk RNA analysis to biopsies (n = 23 and 63, respectively) from ulcerative colitis patients (n = 31) before and after tofacitinib treatment. Response was assessed using endoscopic and clinical criteria. In vitro-derived macrophages and primary intestinal fibroblasts were used to validate our findings.<h4>Results</h4>Forty percent of patients responded to tofacitinib. Responders exhibited higher baseline JAK-STAT activity, while non-responders had increased baseline NF-kB pathway activation. Response was associated with significant changes in the abundance and/or activation of immune, epithelial, and stromal cells and the downregulation of S100A9, FCGR3A, MMP12 in resident macrophages. In contrast, non-responders showed a significant increase in the number and activation of macrophages and fibroblasts following tofacitinib treatment, including upregulation of MMP9, IL1B, IL6, CXCL1, CXCL8, and S100A9 compared to baseline. In monocyte-derived macrophages tofacitinib drove the hyperactivation of macrophages in response to lipopolysaccharide, but not TNF or IFNγ. This effect is dependent on the inhibition of IL-10 signaling, which is abundantly induced in response to LPS, but not to TNF or IFNγ. In contrast, cultured fibroblasts, which produced no IL-10 regardless of the stimuli, showed no hyperactivation when pre-treated with tofacitinib.<h4>Conclusions</h4>We conclude that resistance to tofacitinib is mediated by the hyperactivation of myeloid cells and we identify IL-10-dependent macrophages as one cellular subset contributing to this resistance.

doi:10.1093/ecco-jcc/jjaf076 ↗ PMID 40320713 ↗ PMC12137895 ↗

Study facts

Organism
Homo sapiens
Platform
10x Genomics Chromium
Age group
adult
Disease groups
—
Anatomical sites
colon, rectum, sigmoid colon

Data availability

  • Raw counts
  • Processed matrix
  • Analysis code

File types MTXTSV

Strengths & limitations for reuse

Strengths

  • Raw counts are advertised
  • Processed matrices are advertised
  • Analysis code is available
  • Participant mapping is available
  • Participant counts are documented

Limitations

  • Not documented: cell metadata are advertised
Extraction evidence & provenance

Each extracted field is shown with the source excerpt and location used to resolve it.

Assay

FieldValueEvidence
assay.assay_type single-cell RNA sequencing
Single-cell RNA sequencing of intestinal cells

Section 2.6, offset —
assay.platform 10x Genomics Chromium
loaded onto the Chromium10x Genomics platform

Section 2.6, offset —
assay.reference_genome GRCh38 p10
Gencode release 27, assembly GRCh38 p10

Section 2.7, offset —
assay.sequencing_type scrna_seq
Single-cell RNA sequencing of intestinal cells

Section 2.6, offset —

Cohort

FieldValueEvidence
cohort.age_group adult
Adult

Section —, offset —
cohort.disease_activity_metadata_available True
Thirty-one patients with moderate-to-severe UC starting tofacitinib treatment

Section 3.1, offset —
cohort.study_design longitudinal from source
Timepoint/visit characteristics vary within subjects

Section GEO family SOFT, offset —
cohort.total_participants 11 computed
11 distinct subject/participant IDs across GEO samples

Section GEO family SOFT, offset —
cohort.treatment_exposure_documented True from source
GEO sample characteristics document treatment/therapy

Section GEO family SOFT, offset —
cohort.treatment_response_metadata_available True
Response was defined as a decrease in the endoscopic Mayo score of at least 1 point from baseline

Section 2.3, offset —

Data_Assets

FieldValueEvidence
data_assets.analysis_code True
The analysis code can be found at our GitHub website https://github.com/ibd-bcn/tofacitinib_ibd

Section 2.26, offset —
data_assets.open_access True
"license": "cc by-nc"

Section —, offset —
data_assets.participant_metadata True
"patient": "TOF_005"

Section —, offset —
data_assets.processed_matrix True
matrix.mtx.gz

Section —, offset —
data_assets.raw_counts True inferred
gene counting and aggregation were made using the Cell Ranger software v3.1

Section —, offset —

Processing

FieldValueEvidence
processing.batch_correction_reported True
To correct batch effects across samples, we applied Harmony

Section 2.9, offset —
processing.cell_type_annotation_method marker gene-based annotation using FindAllMarkers
Markers defining each cell type are summarized in Tables S2 and S3

Section 2.10, offset —
processing.doublet_detection_reported True
doublets were assessed using the scDblFinder R package

Section 2.7, offset —
processing.normalization_method logarithmic normalization
We then logarithmically normalized them

Section 2.7, offset —
processing.quality_control_reported True
we filtered the low-quality cells based on the mitochondrial RNA percentage and the number of genes per cell

Section 2.7, offset —

Specimens

FieldValueEvidence
specimens.anatomical_sites ['colon', 'rectum', 'sigmoid colon']
collected from the involved sigmoid colon (or rectum in the case of isolated proctitis)

Section 2.4, offset —
specimens.inflamed_status_available True inferred
baseline, and after receiving tofacitinib treatment for at least 8 weeks

Section 3.2, offset —
specimens.number_of_cells 69813
A total of 69,813 high-quality single cells were considered for the analysis.

Section 2.7, offset —
specimens.number_of_samples 23
We generated scRNA-seq data ... from 23 colonic samples

Section 3.2, offset —
specimens.participant_to_sample_mapping_available True
"patient": "TOF_005"

Section —, offset —
specimens.specimen_type biopsy
Endoscopic colonic biopsies (4-8 from each patient) were collected

Section 2.4, offset —