ArticleCell communication and signaling : CCS2024
BTN3A1 expressed in cervical cancer cells promotes Vγ9Vδ2 T cells exhaustion through upregulating transcription factors NR4A2/3 downstream of TCR signaling.
Article in Cell communication and signaling : CCS, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed.
- The development of novel chimeric antigen receptor gamma-delta T cells against multiple myeloma and single-cell RNA sequencing analysis.British journal of haematology · 2026Article
- γδ T cells and cancer.The Journal of clinical investigation · 2026Review
- T Cell Exhaustion in Cancer Immunotherapy: Heterogeneity, Mechanisms, and Therapeutic Opportunities.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Review
- Modulating tumor-associated macrophages through APP-CD74 blockade with IL4R-exosomes synergizes with PD-1 inhibition in gastric cancer.NPJ precision oncology · 2026Article
- Integrated Multi-Omics Analyses Identify TYMP as a Candidate Protective Immunoregulatory Marker in CD4⁺ T Cells During Sepsis.Journal of inflammation research · 2026Article
- Orphan nuclear receptor 4A1 (NR4A1) and NR4A2 are endogenous regulators of CD71 and their ligands induce ferroptosis in breast cancer.Cell death & disease · 2025Article
- NR4A3high mast cells promote ovarian cancer metastasis by reprogramming tumor-associated macrophages via JAK2/STAT6 signaling.Translational oncology · 2025Article
- Advances and obstacles of T cell-based immunotherapy in gynecological malignancies.Molecular cancer · 2025Review
- γδ T cells in diabetes mellitus: dual roles and therapeutic implications.Frontiers in immunology · 2025Review
- Network pharmacology and UHPLC-HRMS reveal the mechanism of QSFZYL and BMSCs overexpressing IFN-γ against lung adenocarcinoma.Frontiers in immunology · 2025Article
- Multi-omics analysis identifies PTTG1 as a prognostic biomarker associated with immunotherapy and chemotherapy resistance.BMC cancer · 2024Article
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16 authors.
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Abstract
backgroundClinical trials have shown that immunotherapy based on Vγ9Vδ2 T cells (Vδ2 T cells) is safe and well-tolerated for various cancers including cervical cancer (CC), but its overall treatment efficacy remains limited. Therefore, exploring the mechanisms underlying the suboptimal efficacy of Vδ2 T cell-based cancer immunotherapy is crucial for enabling its successful clinical translation.
methodsTumor samples from CC patients and CC cell line-derived xenograft (CDX) mice were analyzed using flow cytometry to examine the exhausted phenotype of tumor-infiltrating Vδ2 T cells. The interrelationship between BTN3A1 expression and Vδ2 T cells in CC, along with their correlation with patient prognosis, was analyzed using data from The Cancer Genome Atlas (TCGA) database. CC cell lines with BTN3A1 knockout (KO) and overexpression (OE) were constructed through lentivirus transduction, which were then co-cultured with expanded Vδ2 T cells, followed by detecting the function of Vδ2 T cells using flow cytometry. The pathways and transcription factors (TFs) related to BTN3A1-induced Vδ2 T cells exhaustion and the factors affecting BTN3A1 expression were identified by RNA-seq analysis, which was confirmed by flow cytometry, Western Blot, and gene manipulation.
resultsTumor-infiltrating Vδ2 T cells exhibited an exhausted phenotype in both CC patients and CDX mice. BTN3A1 expressed in CC is highly enhancing exhaustion markers, while reducing the secretion of effector molecules in Vδ2 T cells. Blocking TCR or knocking down nuclear receptor subfamily 4 group A (NR4A) 2/3 can reverse BTN3A1-induced exhaustion in Vδ2 T cells. On the other hand, IFN-γ secreted by Vδ2 T cells promoted the expression of BTN3A1 and PD-L1.
conclusionsThrough binding γδ TCRs, BTN3A1 expressed on tumor cells, which is induced by IFN-γ, can promote Vδ2 T cells to upregulate the expression of TFs NR4A2/3, thereby affecting their activation and expression of exhaustion-related molecules in the tumor microenvironment (TME). Therefore, targeting BTN3A1 might overcome the immunosuppressive effect of the TME on Vδ2 T cells in CC.
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