{"database":"GEO","file_versions":[{"headers":{"Content-Type":["application/json"]},"body":{"files":{"Other":["ftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE303nnn/GSE303446/"]},"type":"primary"},"statusCode":"OK","statusCodeValue":200}],"scores":null,"additional":{"omics_type":["Transcriptomics"],"species":["Homo sapiens"],"gds_type":["Expression profiling by high throughput sequencing"],"full_dataset_link":["https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE303446"],"repository":["GEO"],"entry_type":["GSE"],"additional_accession":[]},"is_claimable":false,"name":"Beyond CD30 Targeting: Brentuximab Vedotin Triggers Immunogenic Cell Death and Antitumor Immunity in Mycosis Fungoides, Overcoming Resistance via BCL2 Inhibition","description":"Background: Mycosis fungoides (MF), the most common subtype of cutaneous T cell lymphoma (CTCL), has poor prognosis in advanced stages due to lack of effective therapies. Brentuximab vedotin (BV), an antigen-drug conjugate targeting CD30, is approved for CD30+ MF after prior systemic treatment. However, many patients develop resistance with unclarified mechanisms. Method: We conducted single-cell RNA sequencing on 13 paired tumor samples from 6 CD30+ MF patients treated with BV. Eight post-treatment samples were grouped into responsive (n = 5) and non-responsive (n = 3) lesions based on pathologic response. Combination effects of BV and BCL2 inhibitors were assessed in CD30+ CTCL cell lines. Result: BV induced immunogenic cell death (ICD) in both CD30+ and CD30- malignant T cells, enhancing their MHC-II-mediated antigen presentation in responsive lesions. Besides, BV specifically enhanced the IFNα/γ responses in CD30- malignant T cells. These coincided with TME reprogramming: diminished immunosuppressive function of Tregs and activated antitumor immunity mediated by dendritic cells, CD8+ T and NK cells. In non-responsive lesions, resistance was driven by distinct mechanisms: CD30+ malignant T cells upregulated the drug efflux transporter ABCB1 and exhibited impaired endosomal processing, while CD30- tumor cells overexpressed the anti-apoptotic protein BCL2 and displayed blunted IFN response. We confirmed potent synergy between BV and BCL2 inhibitors in CTCL cell lines, overcoming resistance. Conclusion: Beyond direct CD30+ targeting, BV transforms the immunosuppressive milieu by inducing ICD in tumor cells and suppressing Tregs. Resistance involves ABCB1 upregulation in CD30+ cells and BCL2-mediated survival in CD30- cells. Combining BV with BCL2 inhibitors represents a promising strategy to overcome resistance in CD30+ CTCL.","dates":{"publication":"2026/05/20"},"accession":"GSE303446","cross_references":{"GSM":["GSM9126891","GSM9126890","GSM9126895","GSM9126894","GSM9126893","GSM9126892","GSM9126888","GSM9126899","GSM9126898","GSM9126897","GSM9126896","GSM9126889","GSM9126900"],"GPL":["24676"],"GSE":["303446"],"taxon":["Homo sapiens"],"PMID":["[41762706]"]}}