Ask about this productRelated genes to: VTCN1 protein
- Gene:
- VTCN1 NIH gene
- Name:
- V-set domain containing T cell activation inhibitor 1
- Previous symbol:
- -
- Synonyms:
- B7-H4, FLJ22418, B7S1, B7x, B7H4
- Chromosome:
- 1p13.1-p12
- Locus Type:
- gene with protein product
- Date approved:
- 2005-02-25
- Date modifiied:
- 2019-03-06
Related products to: VTCN1 protein
Related articles to: VTCN1 protein
- Experimental validation and functional optimization remain bottlenecks in AI-based protein design. We present a scalable workflow for developing AI-designed minibinders against cancer-associated surface proteins. Screening thousands of designs using mammalian cell-surface display identifies several high-affinity PD-L1 minibinders but far fewer for CD276 (B7-H3) and VTCN1 (B7-H4), highlighting substantial target dependence. Interface predicted template modeling (ipTM) scores generated by Chai-1 with ESM embeddings correlate with binding success and capture deleterious effects of interface mutations. Fluorophore-labeled AI-minibinders enable flow-cytometric staining comparable to conventional antibodies. However, when incorporated into chimeric antigen receptors (CAR), some show poor cell-surface trafficking and limited functionality. Redesign through a genetic algorithm-based diversification strategy that preserves the binding interface while changing non-binding surfaces experimentally reveals an isoelectric point (pI) window that improves CAR expression and enhances target-selective tumor cell killing. Our findings identify biochemical optimization beyond the binding interface as a critical requirement for translating AI-minibinders into functional applications. - Source: PubMed
Publication date: 2026/08/20
Broske BiancaMcEnroe Benjamin AFrechen Sophie CKempchen Tim NFandrey Caroline ITan ElisabethFerber DominicYong Michelle C RKleinert MarieMessmer Julia MKonopka PeterHoch AlexanderBlumenstock KatjaTödtmann Jan M POldenburg JohannesRühl HeikoSemaan AlexanderToma Marieta IMarkova KristinaKobold SebastianRollenske TimGeyer MatthiasMenzel StephanBald TobiasSchmid-Burgk Jonathan LHagelueken GregorHölzel Michael - Small bowel gastrointestinal stromal tumors (GISTs) are more aggressive than gastric GISTs, yet the biologic basis for this difference remains poorly understood. We hypothesized that differential expression of immune checkpoints contributes to this site-specific behavior. Bulk RNA sequencing of 42 primary GISTs (36 gastric, 6 small bowel) revealed marked upregulation of , which encodes the inhibitory checkpoint B7-H4, in small bowel tumors (logFC = 7.95, adjusted < 0.001). In contrast, expression of the therapeutically targeted checkpoints PD-L1, PD-1, and CTLA-4 was comparable between sites. Concordantly, B7-H4 enrichment was accompanied by an immunosuppressive tumor microenvironment, characterized by reduced antigen-presenting cells, fewer effector-memory CD8 T cells, lower granzyme B expression, and suppression of interferon and inflammatory signaling pathways. Notably, the differences in B7-H4 expression were independent of imatinib-treatment status. These findings were corroborated in an external cohort of 77 untreated GISTs, in which was similarly enriched in small bowel tumors. Independent immunohistochemical analysis of a tissue microarray comprising 68 untreated primary GISTs confirmed the pattern, showing median B7-H4 positivity of 78.6% in duodenal, 20.5% in jejunal/ileal, and 0% in gastric tumors, with staining localized to tumor cells rather than stroma. Collectively, these data identify B7-H4 as a site-specific feature of small bowel GISTs and a potential therapeutic target for tumors that have not responded to conventional checkpoint blockade. - Source: PubMed
Publication date: 2026/08/08
Singer HenryMorris MontanaMaestro RobertaTos Angelo Paolo DeiDeMatteo Ronald PVitiello Gerardo A - Thyroid cancer is the most common endocrine malignancy. Although surgery remains the primary treatment, advanced disease frequently recurs or metastasizes, and subsequent therapies yield suboptimal outcomes. Immunotherapy holds promise, yet the underlying immune-evasion mechanisms remain incompletely understood. HBO1, a multifunctional acyltransferase, plays a significant role in tumor immune regulation. Our previous research revealed that HBO1 is highly expressed in thyroid cancer tissues, promotes malignant progression, and inhibits CD8 T cell function. To further elucidate the role and mechanism of HBO1 in thyroid cancer immune regulation, we conducted the following investigations. Firstly, using an in vitro co-culture model analyzed by flow cytometry and ELISA assays, we found that HBO1 overexpression induces CD8 T cell apoptosis and significantly suppresses their cytotoxic function and secretion of effector molecules. Secondly, leveraging bioinformatic analysis of CUT&Tag datasets combined with in vitro cellular experiments, we found that HBO1 was associated with increased VTCN1 expression in an H3K14 acetylation-dependent manner, thereby contributing to CD8 T cell dysfunction. Subsequently, employing RNA-seq analysis, ChIP-qPCR, dual-luciferase reporter assays, co-immunoprecipitation (Co-IP), and in vivo experiments, we further explored the underlying mechanism and found that HBO1 may facilitate BRD4 enrichment at the VTCN1 promoter through H3K14 acetylation, thereby promoting VTCN1 transcription and contributing to anti-tumor immune suppression in thyroid cancer. Finally, through IP-MS and Co-IP experiments, we identified the E3 ligase TRIM21 as a potential upstream regulator of HBO1. TRIM21 modulates HBO1 acetyltransferase activity by promoting its ubiquitination-mediated degradation, consequently influencing HBO1-associated immune escape in thyroid cancer. In summary, this study suggests that HBO1 may regulate VTCN1 expression through an H3K14ac-BRD4-associated mechanism in thyroid cancer, thereby contributing to suppression of CD8 T cell anti-tumor immunity. In addition, TRIM21 may participate in the regulation of HBO1 protein stability and its associated immune-related signaling. Our findings provide new experimental evidence for understanding immune escape mechanisms and exploring potential immunotherapeutic targets in thyroid cancer. - Source: PubMed
Publication date: 2026/07/17
Chen YanZeng FengLiao ShanLei YanHe QianZhou YanhongLi YanlingLong Chen - Tissue factor (TF; encoded by F3) is frequently overexpressed in ovarian clear cell carcinoma (OCCC), but the biological features of TF-high tumors and their therapeutic implications remain poorly defined. We analyzed F3-high and F3-low OCCC using bulk RNA sequencing (n = 112) and single-nucleus RNA sequencing (n = 6; three F3-high and three F3-low cases). Bulk transcriptomic analysis showed enrichment of MYC and cell-cycle pathways in F3-high tumors, whereas immune and inflammatory pathways were enriched in F3-low tumors. Single-nucleus RNA sequencing showed that F3-high tumors contained fewer immune cells and that malignant epithelial cells displayed attenuated interferon-related programs. Transcriptomic analysis identified VTCN1, which encodes B7-H4, as upregulated in F3-high tumors and positively associated with F3 expression. Based on these findings, we evaluated TF and B7-H4 expression by immunohistochemistry in a subset of tumors (n = 56), confirming their co-expression at the protein level. In patient-derived models, higher TF expression was associated with greater sensitivity to tisotumab vedotin (TV) in vitro, and TV treatment significantly suppressed xenograft growth in vivo. These findings support TF-high OCCC as an immune-cold subgroup characterized by proliferative transcriptional programs, frequent B7-H4 co-expression, and preclinical sensitivity to TV. - Source: PubMed
Publication date: 2026/07/12
Mori YutaroTamura RyoTakahashi KotaroYamawaki KaoruIshiguro TatsuyaMotoyama TeiichiOkamoto KojiYoshihara Kosuke - B7-H4 is an emerging immunoregulatory checkpoint broadly overexpressed across solid tumors and minimally present in normal tissues, making it an attractive candidate for targeted imaging and therapy. Here, we develop and evaluate a B7-H4-directed radiotheranostic antibody labeled with [Zr] for PET imaging and with either [Lu] or [Ac] for β- or α-particle therapy, respectively. [Zr]-immunoPET enabled quantitative, whole-body visualization of B7-H4 expression and reliably distinguished high, intermediate, and negative-expressing tumors. Radiotherapy with [Lu]- or [Ac]-conjugated antibody exhibited potent, antigen-dependent antitumor activity, including complete and durable regressions in B7-H4-high expressing xenografts after a single administration, while having a minimal effect on B7-H4-negative tumors. Both therapeutic constructs were well tolerated, causing only transient, reversible myelosuppression without sustained hepatic, renal, or histopathologic toxicity. These findings identify B7-H4 as a promising target for integrated imaging and radionuclide therapy and provide a preclinical foundation for the future development of B7-H4-directed radiotheranostic strategies. - Source: PubMed
Publication date: 2026/07/01
Ghaemi BehnazOlkowski Colleen PBasuli FalguniShi JianfengChoyke Peter LJacobson Orit