Gene expression profile at the single-cell level of skin and PBMC samples collected from patients with severe cutaneous adverse drug reactions (SCADR).
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE235512 | GEO | 2026/06/01
REPOSITORIES: GEO
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Project description:Immune checkpoint inhibitors (ICI) represent new anticancer agents and have been used worldwide. However, ICI can potentially induce life-threatening severe cutaneous adverse reaction (SCAR), such as Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), hindering continuous ICI therapy. We examined 6 cohorts within 25 ICI-induced SJS/TEN patients and conducted single-cell RNA sequencing (scRNA-seq) analysis, which revealed overexpression of macrophage-derived CXCL10 that recruited CXCR3+ cytotoxic T lymphocytes (CTL) in blister cells from ICI-SJS/TEN skin lesions. ScRNA expression profiles and ex vivo blocking studies further identified TNF signaling as the key pathway responsible for macrophage-derived CXCL10 and CTL activation. Based on the trajectory analysis, ICI-activated T cells from whole blood are proposed to serve as the initial cells involved in inflammation, that lead to monocytes differentiating into macrophages and increasing their susceptibility to migrate to the lesion sites. Compared with systemic corticosteroids treatment, ICI-induced SJS/TEN patients treated with biologic TNF blockade showed a significantly rapid recovery and no recurrence of SCAR with continuous ICI therapy. Our findings identified that macrophage-eliciting CTL contribute the pathogenesis of ICI-induced epidermal necrolysis and provide the therapeutic targets for the management and prevention of SCAR induced by ICI therapy.
2024-08-26 | GSE273720 | GEO
Project description:Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life-threatening adverse drug reactions characterized by massive epidermal necrosis, in which the specific danger signals involved remain unclear. Here we show that blister cells from skin lesions of SJS-TEN primarily consist of cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells, and both blister fluids and cells were cytotoxic. Gene expression profiling identified granulysin as the most highly expressed cytotoxic molecule, confirmed by quantitative PCR and immunohistochemistry. Granulysin concentrations in the blister fluids were two to four orders of magnitude higher than perforin, granzyme B or soluble Fas ligand concentrations, and depleting granulysin reduced the cytotoxicity. Granulysin in the blister fluids was a 15-kDa secretory form, and injection of it into mouse skin resulted in features mimicking SJS-TEN. Our findings demonstrate that secretory granulysin is a key molecule responsible for the disseminated keratinocyte death in SJS-TEN and highlight a mechanism for CTL- or NK cell—mediated cytotoxicity that does not require direct cellular contact.
2008-12-04 | GSE13726 | GEO
Project description:Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life-threatening adverse drug reactions characterized by massive epidermal necrosis, in which the specific danger signals involved remain unclear. Here we show that blister cells from skin lesions of SJS-TEN primarily consist of cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells, and both blister fluids and cells were cytotoxic. Gene expression profiling identified granulysin as the most highly expressed cytotoxic molecule, confirmed by quantitative PCR and immunohistochemistry. Granulysin concentrations in the blister fluids were two to four orders of magnitude higher than perforin, granzyme B or soluble Fas ligand concentrations, and depleting granulysin reduced the cytotoxicity. Granulysin in the blister fluids was a 15-kDa secretory form, and injection of it into mouse skin resulted in features mimicking SJS-TEN. Our findings demonstrate that secretory granulysin is a key molecule responsible for the disseminated keratinocyte death in SJS-TEN and highlight a mechanism for CTL- or NK cell—mediated cytotoxicity that does not require direct cellular contact.
2008-12-04 | GSE13727 | GEO
Project description:Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis; (TEN) are life-threatening adverse drug reactions characterized; by massive epidermal necrosis, in which the specific danger; signals involved remain unclear. Here we show that blister; cells from skin lesions of SJS-TEN primarily consist of cytotoxic; T lymphocytes (CTLs) and natural killer (NK) cells, and both; blister fluids and cells were cytotoxic. Gene expression profiling; identified granulysin as the most highly expressed cytotoxic; molecule, confirmed by quantitative PCR and immunohistochemistry. Granulysin concentrations in the blister fluids; were two to four orders of magnitude higher than perforin,; granzyme B or soluble Fas ligand concentrations, and depleting; granulysin reduced the cytotoxicity. Granulysin in the blister; fluids was a 15-kDa secretory form, and injection of it into; mouse skin resulted in features mimicking SJS-TEN. Our; findings demonstrate that secretory granulysin is a key molecule; responsible for the disseminated keratinocyte death in SJS-TEN; and highlight a mechanism for CTL- or NK cellâmediated; cytotoxicity that does not require direct cellular contact. Experiment Overall Design: Blood samples were obtained from 5 different patients with SJS/TEN. The peripheral blood mononuclear cells (PBMCs) were isolated from the whole blood samples by Ficoll-Isopaque (Pharmacia Fine Chemicals) density gradient centrifugation. Total RNA from PBMC was isolated using the RNeasy kit (Qiagen). The 28S and 18S ribosomal RNA peak ratios were determined using microfluidics technology (Agilent). RNA was subjected to reverse transcription using the Superscript II kit (Invitrogen), and the cleaned cRNA was then hybridized to an Affymetrix human genome U133 plus 2.0 array.
2009-01-13 | E-GEOD-13727 | biostudies-arrayexpress
Project description:Background/Objectives: Immune-related cutaneous adverse events (ircAE) are common complications of cancer immunotherapy and provide insight into immune-related ad-verse events (irAE) more broadly. To enhance our molecular understanding, we char-acterized ircAE resulting from single-agent (PD1) and combined immunotherapy reg-imens (P+C). Clinically, maculopapular rashes (MPR) and toxic epidermal necrolysis (TEN) resemble ircAE, providing a valuable basis for investigations. Methods: To in-vestigate the transcriptome and immune infiltrates in ircAE, we conducted transcriptomic analyses and multiplexed immunohistochemistry on skin biopsies from patients re-ceiving PD1 and P+C, as well as those with MPR, TEN, and healthy controls. Results: Principal component analysis revealed distinct transcriptomic clustering between ircAE, MPR, and TEN. Specifically, PD1 ircAE exhibited a gene expression profile similar to TEN, with upregulation of Type-I-response-related genes (e.g., CXCL9 Log2FC 5.34, p<0.0001, CXCL10 Log2FC 6.03, p<0.0001), while P+C ircAE more closely resembled MPR. Immune infiltrates differed significantly between all groups (p=0.002 by PER-MANOVA for all groups). CD4 T-cells were abundant in the dermis of ircAE from any type of immunotherapy. However, PD1 stained positive in 1.07% of CD4 cells with PD1 monotherapy, compared to 0.3%, 0.4%, and 0.08% in P+C, MPR, and TEN, respectively. Conclusions: This study identified distinct molecular and cellular signatures in ircAE depending on the type of immune checkpoint blockade. aPD1-associated ircAE share similarities with the cytotoxic profile of TEN, while P+C more closely mirrored MPR. These findings support the need for tailored management strategies for ircAE, emphasizing personalized therapeutic approaches to minimize treatment interruptions while preserving the efficacy of cancer immunotherapy.
2025-06-25 | GSE297863 | GEO
Project description:Neoadjuvant anlotinib combined with PD-1 blockade therapy can prolong the survival of patients, but the underlying mechanisms for the failure of patients to benefit from combination therapy remain to be explored. To explore the mechanism of drug resistance and predict patient response, we performed scRNA-seq from 6 NSCLC patients, including 3 post-treatment patients with major pathological response (MPR), and 3 Non-MPR patients to observe and analyze the dynamic changes of immune cells, stromal cells and cancer cells from the NSCLC patients who received neoadjuvant anlotinib combined with PD-1 blockade therapy and verified in an independent cohort.
2025-03-31 | GSE291670 | GEO
Project description:Activated B cells play a key role in the pathogenesis of Sjögren’s syndrome (SjS) through the production of autoantibodies and the development of ectopic germinal centers in the salivary glands and other affected sites. Around 5-10% of SjS patients develop B-cell lymphoma, usually extranodal marginal zone lymphomas (eMZL) of the mucosa-associated lymphoid tissue (MALT). The aim of the current study is to screen for the eMZL clonotype in prediagnostic blood and tissue biopsies of SjS patients. We studied prediagnostic tissue biopsies of 3 SjS patients diagnosed with eMZL through immunoglobulin (IG) gene repertoire sequencing. In all 3 cases, we observed the eMZL clonotype in prediagnostic tissue biopsies. To evaluate if skewing in the IGH repertoire may also be detected in the peripheral blood, we sequenced a peripheral blood mononuclear cell (PBMC) sample drawn at eMZL diagnosis and 2 years prior to eMZL relapse in two SjS patients. The eMZL clonotype was detected in the peripheral blood prior to diagnosis for both cases. Next, we selected 3 SjS patients who developed eMZL lymphoma and 3 additional SjS patients who remained cancer-free. We sequenced the IG heavy chain (IGH) gene repertoire in PBMC samples taken a median of 3 years before eMZL diagnosis. In 2 out of 3 eMZL patients, the dominant clonotype in the prediagnostic PBMC samples matched the eMZL clonotype in the diagnostic biopsy. The eMZL clonotypes observed utilized stereotypic IGHV gene combinations (IGHV1-69/IGHJ4 and IGHV4-59/IGHJ5) associated with rheumatoid factor activity, a previously reported feature of eMZL in SjS. Notably, no significant abnormalities were observed in the IGH gene repertoire of the controls. In conclusion, our results indicate that immunogenetic sequencing of the IGH gene repertoire may be an effective method of early detection of eMZL in SjS patients.
2023-04-12 | GSE221412 | GEO
Project description:Based on the prior knowledge of involvement of the human leukocyte antigen locus in Han Chinese patients with carbamazepine-induced Stevens-Johnson syndrome, we imputed the HLA types for each case and control subject from the array of SNPs in the Human610-Quad GWAS platform (NCBI Build 36.1). We then performed a genome-wide association test which included the imputed HLA alleles as markers.
| EGAS00000000036 | EGA