Reverse translational discovery reveals dysregulation of CD4+ and CD8+ resident memory T, myeloid, and stromal cells in steroid-refractory, checkpoint inhibitor colitis
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE253723 | GEO | 2024/03/20
REPOSITORIES: GEO
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Project description:Checkpoint inhibitor colitis (CPI colitis) is a frequent immune-related adverse event resulting from cancer immunotherapy that is currently treated with empiric immunosuppression such as corticosteroids. A greater understanding of the pathogenesis of CPI colitis in the steroid-refractory setting is required to develop better colitis interventions targeted to each patient. Using paired colon biopsies and blood from steroid-experienced patients with endoscopically confirmed CPI colitis, combined with control patients, we performed multiplexed single-cell transcriptomics (scRNA/TCRseq) and proteomics (CITEseq, CyTOF) to identify contributing immune and non-immune populations. In CPI colitis patient biopsies compared to healthy controls, we found enrichment of resident memory (RM) T cells in both the CD8+ and unexpectedly the CD4+ compartments, as well as cytotoxic CD8+ T cells. These 3 populations expressed exact matching TCR, suggesting that CD4+ RM and CD8+ RM T cells are clonal progenitors that give rise to tissue-destructive cytotoxic effectors. Unbiased CyTOF and confirmatory scRNAseq and CITEseq analysis identifies specific mobilized subpopulations of both cytotoxic CD8+ and CD4+ RM cells that express both activation markers CD38 and HLA-DR, underscoring their pathogenic potential. CPI colitis induces global upregulation of interferon signaling and antigen presentation, as well as epithelial-specific dysregulation of homeostatic pathways (aquaporin/solute transporters) which is shared with ulcerative colitis. However, distinct from ulcerative colitis, CPI colitis involves specific alterations in stromal cell metabolic (NAD+, tryptophan) or extracellular signaling (BMP) pathways that directly impact epithelial cell survival, arguing for distinct therapeutic targeting. Finally, endothelial cells in CPI colitis demonstrate enrichment of the integrin 47 ligand MADCAM-1 (which is targeted by anti-47 antibody vedolizumab to treat colitis). This ligand is enriched in CPI colitis patients who received TNF blockade and anti-CTLA-4, identifying subsets of patients who may be more responsive to vedolizumab treatment. This work identifies putative pathogenic resident memory and cytotoxic T cells, and non-immune stromal and endothelial populations, whose properties may nominate subsets of CPI colitis patients amenable to distinct targeting strategies.
2024-03-20 | GSE253719 | GEO
Project description:Checkpoint inhibitor colitis (CPI colitis) is a frequent immune-related adverse event resulting from cancer immunotherapy that is currently treated with empiric immunosuppression such as corticosteroids. A greater understanding of the pathogenesis of CPI colitis in the steroid-refractory setting is required to develop better colitis interventions targeted to each patient. Using paired colon biopsies and blood from steroid-experienced patients with endoscopically confirmed CPI colitis, combined with control patients, we performed multiplexed single-cell transcriptomics (scRNA/TCRseq) and proteomics (CITEseq, CyTOF) to identify contributing immune and non-immune populations. In CPI colitis patient biopsies compared to healthy controls, we found enrichment of resident memory (RM) T cells in both the CD8+ and unexpectedly the CD4+ compartments, as well as cytotoxic CD8+ T cells. These 3 populations expressed exact matching TCR, suggesting that CD4+ RM and CD8+ RM T cells are clonal progenitors that give rise to tissue-destructive cytotoxic effectors. Unbiased CyTOF and confirmatory scRNAseq and CITEseq analysis identifies specific mobilized subpopulations of both cytotoxic CD8+ and CD4+ RM cells that express both activation markers CD38 and HLA-DR, underscoring their pathogenic potential. CPI colitis induces global upregulation of interferon signaling and antigen presentation, as well as epithelial-specific dysregulation of homeostatic pathways (aquaporin/solute transporters) which is shared with ulcerative colitis. However, distinct from ulcerative colitis, CPI colitis involves specific alterations in stromal cell metabolic (NAD+, tryptophan) or extracellular signaling (BMP) pathways that directly impact epithelial cell survival, arguing for distinct therapeutic targeting. Finally, endothelial cells in CPI colitis demonstrate enrichment of the integrin 47 ligand MADCAM-1 (which is targeted by anti-47 antibody vedolizumab to treat colitis). This ligand is enriched in CPI colitis patients who received TNF blockade and anti-CTLA-4, identifying subsets of patients who may be more responsive to vedolizumab treatment. This work identifies putative pathogenic resident memory and cytotoxic T cells, and non-immune stromal and endothelial populations, whose properties may nominate subsets of CPI colitis patients amenable to distinct targeting strategies.
2024-03-20 | GSE253721 | GEO
Project description:Checkpoint inhibitor colitis (CPI colitis) is a frequent immune-related adverse event resulting from cancer immunotherapy that is currently treated with empiric immunosuppression such as corticosteroids. A greater understanding of the pathogenesis of CPI colitis in the steroid-refractory setting is required to develop better colitis interventions targeted to each patient. Using paired colon biopsies and blood from steroid-experienced patients with endoscopically confirmed CPI colitis, combined with control patients, we performed multiplexed single-cell transcriptomics (scRNA/TCRseq) and proteomics (CITEseq, CyTOF) to identify contributing immune and non-immune populations. In CPI colitis patient biopsies compared to healthy controls, we found enrichment of resident memory (RM) T cells in both the CD8+ and unexpectedly the CD4+ compartments, as well as cytotoxic CD8+ T cells. These 3 populations expressed exact matching TCR, suggesting that CD4+ RM and CD8+ RM T cells are clonal progenitors that give rise to tissue-destructive cytotoxic effectors. Unbiased CyTOF and confirmatory scRNAseq and CITEseq analysis identifies specific mobilized subpopulations of both cytotoxic CD8+ and CD4+ RM cells that express both activation markers CD38 and HLA-DR, underscoring their pathogenic potential. CPI colitis induces global upregulation of interferon signaling and antigen presentation, as well as epithelial-specific dysregulation of homeostatic pathways (aquaporin/solute transporters) which is shared with ulcerative colitis. However, distinct from ulcerative colitis, CPI colitis involves specific alterations in stromal cell metabolic (NAD+, tryptophan) or extracellular signaling (BMP) pathways that directly impact epithelial cell survival, arguing for distinct therapeutic targeting. Finally, endothelial cells in CPI colitis demonstrate enrichment of the integrin 47 ligand MADCAM-1 (which is targeted by anti-47 antibody vedolizumab to treat colitis). This ligand is enriched in CPI colitis patients who received TNF blockade and anti-CTLA-4, identifying subsets of patients who may be more responsive to vedolizumab treatment. This work identifies putative pathogenic resident memory and cytotoxic T cells, and non-immune stromal and endothelial populations, whose properties may nominate subsets of CPI colitis patients amenable to distinct targeting strategies.
2024-03-20 | GSE253720 | GEO
Project description:Reverse translational discovery reveals dysregulation of CD4+ and CD8+ resident memory T, myeloid, and stromal cells in steroid-refractory, checkpoint inhibitor colitis
| PRJNA1066821 | ENA
Project description:Reverse translational discovery reveals dysregulation of CD4+ and CD8+ resident memory T, myeloid, and stromal cells in steroid-refractory, checkpoint inhibitor colitis [biopsy CITEseq]
| PRJNA1066818 | ENA
Project description:Reverse translational discovery reveals dysregulation of CD4+ and CD8+ resident memory T, myeloid, and stromal cells in steroid-refractory, checkpoint inhibitor colitis [biopsy scRNA_TCR-seq]
| PRJNA1066817 | ENA
Project description:Reverse translational discovery reveals dysregulation of CD4+ and CD8+ resident memory T, myeloid, and stromal cells in steroid-refractory, checkpoint inhibitor colitis [blood CITE_TCR-seq]
| PRJNA1066822 | ENA
Project description:Background and aimImmune checkpoint inhibitor (ICI) colitis is an increasingly common problem encountered as the use of checkpoint inhibitors (CPIs) grows in the management of cancers. Corticosteroids and tumour necrosis factor (TNF)-alpha inhibitors are widely recommended in the management of ICI colitis; however, the experience is limited when patients are refractory. Different authors have reported success with vedolizumab, mycophenolate, and cyclosporine. This case series describes our experience with calcineurin inhibitors in the management of corticosteroid and anti-TNF-alpha refractory ICI colitis.MethodsData from electronic medical records were identified and reviewed retrospectively from a cohort of patients treated at a single oncology center. All patients who were identified between March 2018 and May 2020 with ICI colitis refractory to treatment with infliximab and corticosteroids were included.ResultsThere were 11 patients who developed ICI colitis after receiving CPIs for advanced melanoma and required rescue therapy with either cyclosporine or tacrolimus after treatment failure of infliximab. Median age was 53 (±8.48) years, with nine patients (81%) receiving combination Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) / programmed cell death protein 1 (PD-1) immunotherapy. Median time after first CPI infusion to ICI colitis was 4.43 (±19.53) weeks. The median time from onset of symptoms to commencement of rescue therapy with calcineurin inhibitors was 70 days (±66.06). Eight of the 11 patients (72.7%) responded to calcineurin inhibition. In patients who responded, calcineurin inhibitors were continued for a median of 54 (±28.96) days.ConclusionThe calcineurin inhibitors cyclosporine and tacrolimus appear to be a safe and effective option for the management of patients with infliximab-refractory ICI colitis. The therapeutic benefit is observed rapidly, and adverse effects appear to be limited with close monitoring.
| S-EPMC8114988 | biostudies-literature
Project description:We report the first case series of immune checkpoint inhibitors (ICI)-associated colitis successfully treated with fecal microbiota transplantation, with reconstitution of the gut microbiome and a relative increase in the proportion of regulatory T-cells within the colonic mucosa. These preliminary data provide evidence that modulation of the gut microbiome may abrogate ICI-associated colitis.
| S-EPMC6322556 | biostudies-literature
Project description:Immune-related adverse events (irAEs) induced by checkpoint inhibitors are well known. Since fatal outcomes have been reported early detection and adequate management are crucial. In particular, colitis is frequently observed and can result in intestinal perforation. This is the first report of an autoimmune colitis that was treated according to algorithms but became resistant due to a CMV reactivation. The 32-y-old male patient with metastatic melanoma treated within an anti-PD-1/ipilimumab combination study developed severe immune-mediated colitis (CTCAE grade 3) with up to 18 watery stools per day starting 2 weeks after treatment initiation. After improving upon therapy with immunosuppressive treatment (high dose steroids and infliximab) combined with parenteral nutrition diarrhea again exacerbated. Additionally, the patient had asymptomatic grade 3 CTCAE amylase and lipase elevation. Colitis was monitored by weekly endoscopies and colon biopsies were analyzed histologically with CMV staining, multi-epitope ligand cartography (MELC) and qRT-PCR for inflammatory genes. In the course, CMV reactivation was detected in the colon and treated with antiviral medication in parallel to a reduction of corticosteroids. Subsequently, symptoms improved. The patient showed a complete response for 2 y now including regression of bone metastases. CMV reactivation under checkpoint inhibitor therapy in combination with immunosuppressive treatment for autoimmune side effects has to be considered in these patients and if present treated. Potentially, CMV reactivation is underdiagnosed. Treatment algorithms should include CMV diagnostics.
| S-EPMC4938313 | biostudies-literature