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B cells have emerged as central players in the tumor microenvironment (TME) of non-small cell lung cancer (NSCLC). However, although there is clear evidence for their involvement in cancer immunity, scanty data exist on the characterization of B cell phenotypes, bioenergetic profiles and possible interactions with T cells in the context of NSCLC. In this study, using polychromatic flow cytometry, mass cytometry, and spatial transcriptomics we explored the intricate landscape of B cell phenotypes, bioenergetics, and their interaction with T cells in NSCLC. Our analysis revealed that TME contains diverse B cell clusters, including VISTA+ Bregs, with distinct metabolic and functional profiles. Target liquid chromatography-tandem mass spectrometry confirmed the expression of VISTA on B cells. VISTA+ Bregs displayed high metabolic demand and were able to produce different cytokines, including interleukin (IL)-10, transforming growth factor (TGF)-β, IL-6, tumor necrosis factor (TNF), and granulocyte–macrophage colony-stimulating factor (GM-CSF). Spatial analysis showed colocalization of B cells with CD4+/CD8+ T lymphocytes in TME. The computational analysis of intercellular communications that links ligands to target genes, performed by NicheNet, predicted B-T interactions via VISTA-PSGL-1 axis. Colocalization analyses revealed that PSGL-1 T cells and VISTA+ B cells are adjacent in the TME. Notably, tumor infiltrating CD8+ T cells expressing PSGL-1 exhibited enhanced metabolism and cytotoxicity. In NSCLC patients, prediction analysis performed by PENCIL revealed the presence of an association between PSGL-1+CD8+ T cells and VISTA+ Bregs with lung recurrence. Our findings suggest a potential interaction between Bregs and T cells through the VISTA-PSGL-1 axis, that could influence NSCLC recurrence. [ABSTRACT FROM AUTHOR]

In recent years, tumor immunotherapy has become an active research area, with the emergence of immune checkpoint inhibitors (ICIs) revolutionizing immunotherapy. Clinical evidence indicates that programmed cell death protein 1 (PD-1) monoclonal antibodies and other drugs have remarkable therapeutic effects. V-domain Ig suppressor of T-cell activation (VISTA) is a new type of immune checkpoint receptor that is highly expressed in various tumors. It is co-expressed with PD-1, T-cell immunoglobulin domain, mucin domain-3 (Tim-3), T-cell immunoglobulin, and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT) and is associated with prognosis, which suggests that it may be a target for immunotherapy. As an immune checkpoint receptor with no mature drugs, VISTA is highly expressed in acute myeloid leukemia (AML), multiple myeloma (MM), and other hematological malignancies; however, its pathogenic mechanism should be defined to better guide treatment. [ABSTRACT FROM AUTHOR]

Background and Purpose Experimental Approach Key Results The current therapy cannot meet the needs of glioblastoma (GBM). V‐domain immunoglobulin suppressor of T‐cell activation (VISTA) is significantly up‐regulated in GBM patients; however, its therapeutic potential in GBM is still unclear.Flow cytometry was used to detect the expression of VISTA and the co‐expression pattern of VISTA and programmed death receptor 1 (PD‐1) on brain infiltrating lymphocytes of GBM mice. Monoclonal antibody therapy was used to evaluate the therapeutic effect of α‐VISTA monotherapy and α‐VISTA combined with α‐PD‐1 on GBM mice. Transcriptome analysis, flow cytometry, and immunofluorescence were used to detect changes of immune microenvironment in mouse brain tumours. Immunofluorescence and TCGA data analysis were used to further validate the combined treatment strategy on patient data.Compared with normal mice, the frequency of VISTA expression and co‐expression of VISTA and PD‐1 on tumour‐infiltrating lymphocytes (TILs) in tumour‐bearing mice was increased. Anti‐VISTA monotherapy significantly up‐regulated multiple immune stimulation‐related pathways and moderately prolonged mouse survival time. Blocking the immune checkpoint VISTA and PD‐1 significantly prolonged the survival time of mice and cured about 80% of the mice; CD8+ T cells played an important role in this process. In addition, we found that the expression of VISTA and PD‐1 was significantly up‐regulated in GBM patients by immunofluorescence, and patients with high expression of VISTA and PD‐1 were associated with poor overall survival. This combination of blocking the immune checkpoint VISTA and PD‐1 may achieve clinical transformation in GBM. [ABSTRACT FROM AUTHOR]

Immune checkpoints are crucial for regulating immune responses and maintaining self-tolerance, as they play a pivotal role in preventing autoimmunity and facilitating tumor immune evasion. This review concentrates on the immune checkpoint molecules PSGL-1 and VISTA. Both molecules are highly expressed in hematopoietic cells, including T cells and myeloid cells. VISTA functions both as a ligand on myeloid cells, where it regulates cytokine production, chemotaxis, and phagocytosis while promoting their differentiation into a tolerogenic phenotype and as a receptor on T cells, where it contributes to T cell quiescence. PSGL-1, which acts as a binding partner for VISTA, further inhibits T-cell activation and fosters tolerance within the acidic tumor microenvironment. Our review provides a comprehensive analysis of the structure, expression, and biological functions of PSGL-1 and VISTA and emphasizes their therapeutic potential in cancer treatment, autoimmune diseases, and transplantation. The dual role of these checkpoints in immune regulation presents novel opportunities for advancing cancer immunotherapy and developing new strategies for managing autoimmune conditions. [ABSTRACT FROM AUTHOR]

Malignant Mesothelioma is a primary malignant tumor of the mesothelium lining the pleura, pericardium, peritoneum and tunica vaginalis of the testis with a poor prognosis. The epithelioid subtype is graded as high and low grade in the 2021 WHO classification of thoracic tumors. Recently, promising results from clinical trials of treatment with immune checkpoint inhibitors are reported. The aim of our study was to shed light on clinical studies on potential immune checkpoint inhibitors by examining VISTA and PD-L1 expression levels as well as HEG1 in malignant mesothelioma subtypes. Our study included 69 cases diagnosed with 'malignant mesothelioma, well-differentiated papillary mesothelial tumor, atypical mesothelial hyperplasia' at Dicle University Faculty of Medicine Department of Pathology between 2015 and 2021. Primary antibodies against HEG1, VISTA, and PD-L1 were used in the immunohistochemical study. The results showed a significant relationship between PD-L1 expression and sarcomatoid and high-grade epithelioid malignant mesotheliomas. VISTA was detected at a high rate in epithelioid malignant mesotheliomas and was negative in non-mesothelial tumors. HEG1 was positively monitored in mesothelial-derived tumors and negatively monitored in non-mesothelial tumors. The obtained results suggest that HEG1 could be further explored as a useful marker in determining mesothelial origin and that the expression levels of VISTA and PD-L1 markers may vary in histological subtypes in the selection of drugs for the treatment of malignant mesothelioma. [ABSTRACT FROM AUTHOR]

Abstract Immune checkpoints are crucial for regulating immune responses and maintaining self-tolerance, as they play a pivotal role in preventing autoimmunity and facilitating tumor immune evasion. This review concentrates on the immune checkpoint molecules PSGL-1 and VISTA. Both molecules are highly expressed in hematopoietic cells, including T cells and myeloid cells. VISTA functions both as a ligand on myeloid cells, where it regulates cytokine production, chemotaxis, and phagocytosis while promoting their differentiation into a tolerogenic phenotype and as a receptor on T cells, where it contributes to T cell quiescence. PSGL-1, which acts as a binding partner for VISTA, further inhibits T-cell activation and fosters tolerance within the acidic tumor microenvironment. Our review provides a comprehensive analysis of the structure, expression, and biological functions of PSGL-1 and VISTA and emphasizes their therapeutic potential in cancer treatment, autoimmune diseases, and transplantation. The dual role of these checkpoints in immune regulation presents novel opportunities for advancing cancer immunotherapy and developing new strategies for managing autoimmune conditions.

Jianqun Yin,&ast; Jiawei Chen,&ast; Ting Wang, Huiming Sun, Yongdong Yan, Canhong Zhu, Li Huang, Zhengrong Chen Respiratory Department, Children’s Hospital of Soochow University, Suzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Zhengrong Chen; Li Huang, Respiratory Department, Children’s Hospital of Soochow University, No. 303 Jingde Road, Gusu District, Suzhou City, Jiangsu Province, People’s Republic of China, Tel +86-13771721180 ; +86-18962183510, Email chenzhengrong@suda.edu.cn; huanglilcy@163.comObjective: To investigate the significance of VISTA in bronchial asthma and its impact on the disease.Methods: Human peripheral blood of asthma children was gathered. The expression concentrations of VISTA, IL-4, IL-6, CD25, CD40L, and PD-L2 in peripheral blood plasma were detected by ELISA. We established the mouse model of asthma and intervened with agonistic anti-VISTA mAb (4C11) and VISTA fusion protein. ELISA, flow cytometry, and Western blotting were performed to detect the expression levels of Th1, Th2, and Th17 cell subsets and related characteristic cytokines, as well as the protein levels of MAPKs, NF-κB, and TRAF6 in lung tissues. In addition, the infiltration of eosinophils and inflammatory cells, airway mucus secretion, and VISTA protein expression in lung histopathological sections of different groups of mice were analyzed.Results: The concentration of VISTA in human asthma group decreased significantly (p < 0.05); A positive correlation was observed between VISTA and CD40L. The intervention of 4C11 mAb and fusion protein respectively during the induction period increase the differentiation of Th1 cells and the secretion of IFN-γ, and inhibit the differentiation of Th2 and Th17 cells, as well as the secretion of IL-4, IL-5, IL-13 and IL-17, partially reduce the pathological changes of asthma in mouse lungs and correct the progress of asthma. The MAPK, NF-κB, and TRAF6 protein levels were the middle range in the 4C11 mAb and fusion protein groups (p < 0.05).Conclusion: The findings suggest VISTA may play a negative regulatory role in the occurrence and development of bronchial asthma.Keywords: VISTA, bronchial asthma, Th2 cells, cytokines, anti-VISTA mAb, VISTA fusion protein

Background Aim Methods Results Conclusion Severe cutaneous adverse reactions (SCARs) mediated by cytotoxic T lymphocytes are a series of life‐threatening conditions with a mortality of 4%–20%. The clinical application of tumor necrosis factor‐alpha (TNF‐α) antagonist improves the outcome of some SCARs patients; however, this is complicated by the elusive and varied immunopathogenesis.To investigate whether IgE antibody responses to HEMAs are associated with AD, its severity, and response to dupilumab.To clarify the precise process and optimize the therapy regimen of SCARs, we performed single‐cell sequencing, in vitro functional and clinical analysis of patients with SCARs.We observed that TNF‐α breaks drug‐specific T‐cell tolerance by inhibiting the expression of V‐type immunoglobulin domain‐containing suppressor of T‐cell activation (VISTA). Furthermore, TNF‐α generated a positive feedback loop in the early phase of drug‐specific T‐cell activation, whereby B cells acted reciprocally on the corresponding T cells to reinforce TNF‐α cytokine expression. In contrast, this pathway of TNF‐α‐VISTA signaling did not operate in memory effector T cells. Drug‐specific memory effector T‐cell responses were inhibited by increasing Treg cell expression in a negative feedback loop, with TNF‐α antagonists preventing the inhibitory effect. These observations align with the clinical analysis that early but not late intervention with TNF‐α antagonists significantly improved outcomes in SCARs patients.Our findings defining feedback regulation of VISTA and Treg cells by TNF‐α in different stages of the drug‐specific T‐cell response and, indicate that a Treg agonists, instead of TNF‐α antagonists, could be used for treatment of patients with progressive SCARs. [ABSTRACT FROM AUTHOR]

Background: CI-8993 is a fully human IgG1κ monoclonal antibody (mAb) that binds specifically to immune checkpoint molecule VISTA (V-domain Ig suppressor of T-cell activation). Phase I safety has been established in patients with advanced cancer (NCT02671955). To determine the pharmacokinetics and biodistribution of CI-8993 in patients, we aimed to develop 89Zr-labelled CI-8993 and validate PET imaging and quantitation in preclinical models prior to a planned human bioimaging trial. Methods: CI-8993 and human isotype IgG1 control were conjugated to the metal ion chelator p-isothiocyanatobenzyl-desferrioxamine (Df). Quality of conjugates were assessed by SE-HPLC, SDS-PAGE, and FACS. After radiolabelling with zirconium-89 (89Zr), radioconjugates were assessed for radiochemical purity, immunoreactivity, antigen binding affinity, and serum stability in vitro. [89Zr]Zr-Df-CI-8993 alone (1 mg/kg, 4.6 MBq) or in combination with 30 mg/kg unlabelled CI-8993, as well as isotype control [89Zr]Zr-Df-IgG1 (1 mg/kg, 4.6 MBq) were assessed in human VISTA knock-in female (C57BL/6 N-Vsirtm1.1(VSIR)Geno, huVISTA KI) or control C57BL/6 mice bearing syngeneic MB49 bladder cancer tumours; and in BALB/c nu/nu mice bearing pancreatic Capan-2 tumours. Results: Stable constructs with an average chelator-to-antibody ratio of 1.81 were achieved. SDS-PAGE and SE-HPLC showed integrity of CI-8993 was maintained after conjugation; and ELISA indicated no impact of conjugation and radiolabelling on binding to human VISTA. PET imaging and biodistribution in MB49 tumour-bearing huVISTA KI female mice showed specific localisation of [89Zr]Zr-Df-CI-8993 to VISTA in spleen and tumour tissues expressing human VISTA. Specific tumour uptake was also demonstrated in Capan-2 xenografted BALB/c nu/nu mice. Conclusions: We radiolabelled and validated [89Zr]Zr-Df-CI-8993 for specific binding to huVISTA in vivo. Our results demonstrate that 89Zr-labelled CI-8993 is now suitable for targeting and imaging VISTA expression in human trials. [ABSTRACT FROM AUTHOR]

Investigate the feasibility of using deep learning-based accelerated 3D T1-weighted volumetric isotropic turbo spin-echo acquisition (VISTA) for vessel wall magnetic resonance imaging (VW-MRI), compared to traditional Compressed SENSE and optimize acceleration factor (AF) to obtain high-quality clinical images. 40 patients with atherosclerotic plaques in the intracranial or carotid artery were prospectively enrolled in our study from October 1, 2022 to October 31, 2023 underwent high-resolution vessel wall imaging on a 3.0 T MR system using variable Compressed SENSE (CS) AFs and reconstructed by an optimized artificial intelligence constrained Compressed SENSE (CS-AI). Images were reconstructed through both traditional CS and optimized CS-AI. Two radiologists qualitatively assessed the image quality scores of CS and CS-AI across different segments and quantitatively evaluated SNR (signal-to-noise ratio) and CNR (contrast-to-noise ratio) metrics. Paired t-tests, ANOVA, and Friedman tests analyzed image quality metrics. Written informed consent was obtained from all patients in this study. CS-AI groups demonstrated good image quality scores compared to reference scans until AF up to 12 (P < 0.05). The CS-AI 10 protocol provided the best images in the lumen of both normal and lesion sites (P < 0.05). The plaque SNR was significantly higher in CS-AI groups compared to CS groups until the AF increased to 12 (P < 0.05). CS-AI protocols had higher CNR compared to CS with whichever AF on both pre-and post-contrast T1WI (P < 0.05), The CNR was highest in the CS-AI 10 protocol on pre-contrast T1WI and in CS-AI 12 on post-contrast T1WI (P < 0.05). The study demonstrated the feasibility of using CS-AI technology to diagnose arteriosclerotic vascular disease with 3D T1 VISTA sequences. The image quality and diagnostic efficiency of CS-AI images were comparable or better than traditional CS images. Higher AFs are feasible and have potential for use in VW-MRI. The determination of standardized AFs for clinical scanning protocol is expected to help for empirical evaluation of new imaging technology. [ABSTRACT FROM AUTHOR]

Due to the genetic diversity between the mother and the fetus, heightened control over the immune system during pregnancy is crucial. Immunological parameters determined by clinicians in women with idiopathic recurrent spontaneous abortion (RSA) include the quantity and activity of Natural Killer (NK) and Natural Killer T (NKT) cells, the quantity of regulatory T lymphocytes, and the ratio of pro-inflammatory cytokines, which indicate imbalances in Th1 and Th2 cell response. The processes are controlled by immune checkpoint proteins (ICPs) expressed on the surface of immune cells. We aim to investigate differences in the expression of ICPs on T cells, T regulatory lymphocytes, NK cells, and NKT cells in peripheral blood samples collected from RSA women, pregnant women, and healthy multiparous women. We aim to discover new insights into the role of ICPs involved in recurrent pregnancy loss. Peripheral blood mononuclear cells (PBMCs) were isolated by gradient centrifugation from blood samples obtained from 10 multiparous women, 20 pregnant women (11–14th week of pregnancy), and 20 RSA women, at maximum of 72 h after miscarriage. The PBMCs were stained for flow cytometry analysis. Standard flow cytometry immunophenotyping of PBMCs was performed using antibodies against classical lymphocyte markers, including CD3, CD4, CD8, CD56, CD25, and CD127. Additionally, ICPs were investigated using antibodies against Programmed Death Protein-1 (PD-1, CD279), T cell immunoglobulin and mucin domain-containing protein 3 (TIM-3, CD366), V-domain Ig suppressor of T cell activation (VISTA), T cell immunoglobulin and ITIM domain (TIGIT), and Lymphocyte activation gene 3 (LAG-3). We observed differences in the surface expression of ICPs in the analyzed subpopulations of lymphocytes between early pregnancy and RSA, after miscarriage, and in women. We noted diminished expression of PD-1 on T lymphocytes (p = 0.0046), T helper cells (CD3CD4 positive cells, p = 0.0165), T cytotoxic cells (CD3CD8 positive cells, p = 0.0046), T regulatory lymphocytes (CD3CD4CD25CD127 low positive cells, p = 0.0106), and NKT cells (CD3CD56/CD16 positive cells, p = 0.0438), as well as LAG-3 on lymphocytes T (p = 0.0225) T helper, p = 0.0426), T cytotoxic cells (p = 0.0458) and Treg (p = 0.0293), and cells from RSA women. Impaired expression of TIM-3 (p = 0.0226) and VISTA (p = 0.0039) on CD8 cytotoxic T and NK (TIM3 p = 0.0482; VISTA p = 0.0118) cells was shown, with an accompanying increased expression of TIGIT (p = 0.0211) on NKT cells. The changes in the expression of surface immune checkpoints indicate their involvement in the regulation of pregnancy. The data might be utilized to develop specific therapies for RSA women based on the modulation of ICP expression. [ABSTRACT FROM AUTHOR]

We devised a method that combines the 3D-Dixon-gradientecho (GRE) method with an improved motion-sensitized driven-equilibrium (iMSDE) to suppress blood flow signals. The purpose of this study was to evaluate the effectiveness of the new method we developed plaque imaging method (3D-Dixon-GRE with the iMSDE method). Retrospective cohort. Thirty-nine patients who underwent cervical plaque imaging. FIELD STRENGTH/SEQUENCE:3.0 T/3D-GRE. Signal intensities of the common carotid artery, aorta, plaque, muscle, and subcutaneous fat were measured through the VISTA and the 3D-Dixon-GRE with iMSDE methods, and each contrast was calculated. Used the Mann Whitney U test. P -values below 0.05 were considered statistically significant. Plaque and muscle contrast estimated through the VISTA method and 3D-Dixon-GRE with iMSDE method was 1.60 ± 0.96 and 2.04 ± 1.06, respectively, (P < 0.05). The contrast between the flow (common carotid artery and Aorta) and muscle according to the VISTA method and 3D-Dixon-GRE with iMSDE method was 0.24 ± 0.11 and 0.40 ± 0.12, respectively (P < 0.001). Finally, the mean contrast for subcutaneous fat and muscle at six locations was 3.05 ± 1.25 and 0.81 ± 0.23 for the VISTA method and 3D-Dixon-GRE with the iMSDE method, respectively (P < 0.001). Compared to the conventional method (VISTA), the 3D-Dixon-GRE with iMSDE method is preferable in relation to the fat suppression effect, but it is disadvantageous regarding blood flow signal suppression. Therefore, the 3D-Dixon-GRE with the iMSDE method could be considered useful for plaque imaging. [Display omitted] [ABSTRACT FROM AUTHOR]

Background and Aims: This study aim to treat gingival recession defects in the anterior and premolar teeth of the maxilla and mandible by comparing two methods: the coronally advanced flap (CAF) and the vestibular incision subperiosteal tunnel access (VISTA), both of which involve using platelet-rich fibrin (PRF). Materials and Methods: An age range of 18 to 50 years was examined for the study, which included twenty-four participants. The patients were chosen at random from the Outpatient Department of Periodontology at Shree Bankey Bihari Dental College and Research Centre in Masuri-Ghaziabad, U.P. They were divided into two groups of twelve each, and they were all diagnosed with isolated gingival recession defects on human maxillary and mandibular anterior teeth and premolars. Both Group A and Group B had recession defects covered with PRF membranes; however, Group A had a CAF and Group B underwent VISTA. Clinical parameters measured at baseline, 1-month, 3-months, and 6-months postoperative intervals included recession length, recession width, probing depth, width of keratinized tissue, clinical attachment level, and percentage of root coverage. Result: Both groups demonstrated notable enhancements in clinical parameters. However, the values of Group B were more statistically significant (P < 0.05) by showing a reduction in probing depth, recession length, recession width, clinical attachment level, and gain in width of keratinized tissue, as well as a percentage of root coverage, as compared to Group A. Conclusion: The VISTA technique was considered a more conservative approach for treating gingival recession defects with PRF membrane that showed good clinical outcomes and better results.

In recent years, tumor immunotherapy has become an active research area, with the emergence of immune checkpoint inhibitors (ICIs) revolutionizing immunotherapy. Clinical evidence indicates that programmed cell death protein 1 (PD-1) monoclonal antibodies and other drugs have remarkable therapeutic effects. V-domain Ig suppressor of T-cell activation (VISTA) is a new type of immune checkpoint receptor that is highly expressed in various tumors. It is co-expressed with PD-1, T-cell immunoglobulin domain, mucin domain-3 (Tim-3), T-cell immunoglobulin, and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT) and is associated with prognosis, which suggests that it may be a target for immunotherapy. As an immune checkpoint receptor with no mature drugs, VISTA is highly expressed in acute myeloid leukemia (AML), multiple myeloma (MM), and other hematological malignancies; however, its pathogenic mechanism should be defined to better guide treatment.

ABSTRACT: Background and Aims: This study aim to treat gingival recession defects in the anterior and premolar teeth of the maxilla and mandible by comparing two methods: the coronally advanced flap (CAF) and the vestibular incision subperiosteal tunnel access (VISTA), both of which involve using platelet-rich fibrin (PRF). Materials and Methods: An age range of 18 to 50 years was examined for the study, which included twenty-four participants. The patients were chosen at random from the Outpatient Department of Periodontology at Shree Bankey Bihari Dental College and Research Centre in Masuri-Ghaziabad, U.P. They were divided into two groups of twelve each, and they were all diagnosed with isolated gingival recession defects on human maxillary and mandibular anterior teeth and premolars. Both Group A and Group B had recession defects covered with PRF membranes; however, Group A had a CAF and Group B underwent VISTA. Clinical parameters measured at baseline, 1-month, 3-months, and 6-months postoperative intervals included recession length, recession width, probing depth, width of keratinized tissue, clinical attachment level, and percentage of root coverage. Result: Both groups demonstrated notable enhancements in clinical parameters. However, the values of Group B were more statistically significant (P < 0.05) by showing a reduction in probing depth, recession length, recession width, clinical attachment level, and gain in width of keratinized tissue, as well as a percentage of root coverage, as compared to Group A. Conclusion: The VISTA technique was considered a more conservative approach for treating gingival recession defects with PRF membrane that showed good clinical outcomes and better results. [ABSTRACT FROM AUTHOR]

Haiping Xie,1,&ast; Xuexin Zhong,1,&ast; Junlin Chen,2 Shuang Wang,1 Yuefang Huang,2 Niansheng Yang1 1Department of Rheumatology and Clinical Immunology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510080, People’s Republic of China; 2Department of Pediatrics, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510080, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Niansheng Yang, Department of Rheumatology and Clinical Immunology, The First Affiliated Hospital, Sun Yat-sen University, 58 Zhongshan Second Road, Guangzhou, 510080, People’s Republic of China, Tel +86-20-87755766 ext 8150, Email yangnsh@mail.sysu.edu.cnBackground: Interstitial lung disease (ILD), characterized by pulmonary fibrosis (PF), represents the end-stage of various ILDs. The immune system plays an important role in the pathogenesis of PF. V-domain immunoglobulin suppressor of T-cell activation (VISTA) is an immune checkpoint with immune suppressive functions. However, its specific role in the development of PF and the underlying mechanisms remain to be elucidated.Methods: We assessed the expression of VISTA in CD4 T cells from patients with connective tissue disease-related interstitial lung disease (CTD-ILD). Spleen cells from wild-type (WT) or Vsir−/− mice were isolated and induced for cell differentiation in vitro. Additionally, primary lung fibroblasts were isolated and treated with interleukin-17A (IL-17A). Mice were challenged with bleomycin (BLM) following VISTA blockade or Vsir knockout. Moreover, WT or Vsir−/− CD4 T cells were transferred into Rag1−/− mice, which were then challenged with BLM.Results: VISTA expression was decreased in CD4 T cells from patients with CTD-ILD. Vsir deficiency augmented T-helper 17 (Th17) cell differentiation in vitro. Furthermore, IL-17A enhanced the production of inflammatory cytokines, as well as the differentiation and migration of lung fibroblasts. Both VISTA blockade and knockout of Vsir increased the percentage of IL-17A-producing Th17 cells and promoted BLM-induced PF. In addition, mice receiving Vsir−/− CD4 T cells exhibited a higher percentage of Th17 cells and more severe PF compared to those receiving WT CD4 T cells.Conclusion: These findings demonstrate the significant role of VISTA in modulating the development of PF by controlling Th17 cell differentiation. These insights suggest that targeting VISTA could be a promising therapeutic strategy for PF. Keywords: VISTA, lung fibrosis, Th17 cells, IL-17A, fibroblast

Lingtian Weng,1 Xuhong Jiang1,2 1The First School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, People’s Republic of China; 2Development Planning Department, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, People’s Republic of ChinaCorrespondence: Xuhong Jiang, Zhejiang Chinese Medical University, Binwen Road No. 584, Hangzhou, Zhejiang, People’s Republic of China, Tel +8615988890828, Email jiangxuhongtcm@163.com

A checkpoint protein called the V-domain Ig suppressor of T cell activation (VISTA) is important for controlling immune responses. Immune cells that interact with VISTA have molecules, or receptors, known as VISTA receptors. Immune system activity can be modified by the interaction between VISTA and its receptors. Since targeting VISTA or its receptors may be beneficial in certain conditions, VISTA has been studied in relation to immunotherapy for cancer and autoimmune illnesses. The purpose of this study was to examine the expression levels and interactions between VISTA and its receptors, VSIG3 and PSGL-1, in breast cancer tissues. IHC analysis revealed higher levels of proteins within the VISTA/VSIG3/PSGL-1 axis in cancer tissues than in the reference samples (mastopathies). VISTA was found in breast cancer cells and intratumoral immune cells, with membranous and cytoplasmic staining patterns. VISTA was also linked with pathological grade and VSIG3 and PSGL-1 levels. Furthermore, we discovered that the knockdown of one axis member boosted the expression of the other partners. This highlights the significance of VISTA/VSIG3/PSGL-1 in tumor stroma and microenvironment remodeling. Our findings indicate the importance of the VISTA/VSIG3/PSGL-1 axis in the molecular biology of cancer cells and the immune microenvironment. [ABSTRACT FROM AUTHOR]

Although inhibitors targeting the PD1/PD-L1 immune checkpoint are showing comparably good outcomes, a significant percentage of head and neck squamous cell carcinoma (HNSCC) patients do not respond to treatment. Apart from using different treatment strategies, another possibility would be to target other immune checkpoints operating in these non-responding tumors. To obtain an overview of which checkpoint ligands are expressed on HNSCC tumor cells and if these ligands are affected by HGF/MET signaling, we used mRNA sequencing and antibody-based techniques for identifying checkpoint ligands in six HNSCC tumor cell lines. Furthermore, we compared our results to mRNA sequencing data. From the checkpoint ligands we investigated, VISTA was expressed the highest at the RNA level and was also the most ubiquitously expressed. PD-L2 and B7-H3 were expressed comparably lower and were not present in all cell lines to the same extent. B7-H4, however, was only detectable in the Detroit 562 cell line. Concerning the effect of HGF on the ligand levels, PD-L2 expression was enhanced with HGF stimulation, whereas other checkpoint ligand levels decreased with stimulation. B7-H4 levels in the Detroit 562 cell line drastically decreased with HGF stimulation. This is of interest because both the checkpoint ligand and the growth factor are reported to be connected to epithelial–mesenchymal transition in the literature. [ABSTRACT FROM AUTHOR]

Sepsis is a dysregulated systemic immune response to infection i.e. responsible for ∼35% of in-hospital deaths at a significant fiscal healthcare cost. Our laboratory, among others, has demonstrated the efficacy of targeting negative checkpoint regulators (NCRs) to improve survival in a murine model of sepsis, cecal ligation and puncture (CLP). B7-CD28 superfamily member, V-domain immunoglobulin suppressor of T cell activation (VISTA), is an ideal candidate for strategic targeting in sepsis. VISTA is a 35 to 45 kDa type 1 transmembrane protein with unique biology that sets it apart from all other NCRs. We recently reported that VISTA−/− mice had a significant survival deficit post-CLP, which was rescued upon adoptive transfer of a VISTA-expressing pMSCV-mouse Foxp3-EF1α-GFP-T2A-puro stable Jurkat cell line (Jurkat foxp3 T cells). Based on our prior study, we investigated the effector cell target of Jurkat foxp3 T cells in VISTA−/− mice. γδ T cells are a powerful lymphoid subpopulation that require regulatory fine-tuning by regulatory T cells to prevent overt inflammation/pathology. In this study, we hypothesized that Jurkat foxp3 T cells nonredundantly modulate the γδ T cell population post-CLP. We found that VISTA−/− mice have an increased accumulation of intestinal CD69low γδ T cells, which are not protective in murine sepsis. Adoptive transfer of Jurkat foxp3 T cells decreased the intestinal γδ T cell population, suppressed proliferation, skewed remaining γδ T cells toward a CD69high phenotype, and increased soluble CD40L in VISTA−/− mice post-CLP. These results support a potential regulatory mechanism by which VISTA skews intestinal γδ T cell lineage representation in murine sepsis. [ABSTRACT FROM AUTHOR]

Background. Gingival recession (GR) has become one of the most common concerns in oral mucosal diseases. It causes discomfort such as root hypersensitivity, root caries, and aesthetic problems, leading to the development of various surgical techniques to address GRs. This study compared the non-advanced tunnel and m-VISTA techniques in treating multiple GRs. Methods. A literature search related to the efficiency of non-advanced tunnel and m-VISTA techniques was conducted in MEDLINE (PubMed), EMBASE (ScienceDirect), Cochrane Central Register of Controlled Trials (Cochrane Library), Springer Link, and Google Scholar. Randomized controlled trials (RCTs) reporting periodontal parameters published in the recent four years (2019–2023) were included and assessed for the risk of bias. All in vitro, animal, pilot studies, case reports, and case series were excluded. Results. Five RCTs were included with 195 cases of GRs. Comparing the two techniques revealed a significant increase in keratinized tissue width (KTW) from baseline to 6 months (-1.4 mm), in clinical attachment level (CAL) (-2.65 mm), and in recession depth (-2.7 mm) for the tunnel technique. On the other hand, a significant increase in GR width (-2.26 mm) was found in the m-VISTA group. Finally, there were no significant differences in probing depths. Conclusion. Both techniques were effective in root coverage and may be valuable for treating multiple GRs.

Abstract Background VISTA is a well-known immune checkpoint in T cell biology, but its role in innate immunity is less established. Here, we investigated the role of VISTA on anticancer macrophage immunity, with a focus on phagocytosis, macrophage polarization and concomitant T cell activation. Methods Macrophages, differentiated from VISTA overexpressed THP-1 cells and cord blood CD34+ cell-derived monocytes, were used in phagocytosis assay using B lymphoma target cells opsonized with Rituximab. PBMC-derived macrophages were used to assess the correlation between phagocytosis and VISTA expression. qRT-PCR, flow cytometry, and enzyme-linked immunosorbent assay were performed to analyze the impact of VISTA on other checkpoints and M1/M2-like macrophage biology. Additionally, flow cytometry was used to assess the frequency of CD14+ monocytes expressing VISTA in PBMCs from 65 lymphoma patients and 37 healthy donors. Results Ectopic expression of VISTA in the monocytic model cell line THP-1 or in primary monocytes triggered differentiation towards the macrophage lineage, with a marked increase in M2-like macrophage-related gene expression and decrease in M1-like macrophage-related gene expression. VISTA expression in THP-1 and monocyte-derived macrophages strongly downregulated expression of SIRPα, a prominent ‘don’t eat me’ signal, and augmented phagocytic activity of macrophages against cancer cells. Intriguingly, expression of VISTA’s extracellular domain alone sufficed to trigger phagocytosis in ∼ 50% of cell lines, with those cell lines also directly binding to recombinant human VISTA, indicating ligand-dependent and -independent mechanisms. Endogenous VISTA expression was predominantly higher in M2-like macrophages compared to M0- or M1-like macrophages, with a positive correlation observed between VISTA expression in M2c macrophages and their phagocytic activity. VISTA-expressing macrophages demonstrated a unique cytokine profile, characterized by reduced IL-1β and elevated IL-10 secretion. Furthermore, VISTA interacted with MHC-I and downregulated its surface expression, leading to diminished T cell activation. Notably, VISTA surface expression was identified in monocytes from all lymphoma patients but was less prevalent in healthy donors. Conclusions Collectively, VISTA expression associates with and drives M2-like activation of macrophages with a high phagocytic capacity yet a decrease in antigen presentation capability to T cells. Therefore, VISTA is a negative immune checkpoint regulator in macrophage-mediated immune suppression.

Melanoma represents a public health issue. One of the biggest goals of current research is to develop new therapeutic options for patients affected by this aggressive tumor. We conducted a retrospective study including 105 patients diagnosed with cutaneous and ocular melanoma, with stages varying from pT1a to pT4b and pT4e, respectively, and we performed immunohistochemistry reactions with the new potential prognostic marker, VISTA (V-domain Ig suppressor of T cell activation). We quantified the expression by applying the H-score adapted for VISTA and divided the patients, based on the median value, into groups that presented high, low, and negative expression. Therefore, we obtained 65 cases with positive expression for cutaneous melanoma and 8 cases with positive expression for ocular melanoma. Forty-one cases presented high expression in cutaneous melanoma and three cases presented high expression in ocular melanoma. In cutaneous melanoma, analytic statistics showed that VISTA expression was associated with a high Breslow index, high mitotic count, high Ki67 expression, and advanced clinicopathological stage. The majority of ocular melanoma cases demonstrating a positive reaction were classified as stage pT3, whereas earlier stages showed a negative reaction. Our findings underscore a significant correlation between VISTA expression and key prognostic factors in melanoma. Looking ahead, the prospect of future randomized studies holds promise in corroborating the clinical relevance of our findings. By further elucidating the intricate relationship between VISTA expression and melanoma progression, new treatment strategies could be found, improving patient outcomes in this challenging neoplasm. [ABSTRACT FROM AUTHOR]

Introduction: Immunotherapy by blocking immune checkpoints programmed death/ligand (PD1/PDL1) and cytotoxic T-lymphocyte-associated protein 4(CTLA4) has emerged as new therapeutic targets in cancer. However, their efficacy has been limited due to resistance. A new- checkpoint V-domain Ig-containing suppressor of T cell activation (VISTA) has appeared, but the use of its inhibition effect in combination with antibodies targeting PDL1/PD1and CTLA4 has not been reported in ovarian cancer. Methods: In this study, we investigated the expressions of VISTA, CTLA4, and PDL1 using immunohistochemistry (IHC)on 135 Formalin-Fixed Paraffin-Embedded (FFPE)tissue samples of High-grade serous carcinoma (HGSOC). VISTA, CTLA4, PDL1, PD1, CD8, CD4, and FOXP3 mRNA extracted from 429 patients with ovarian cancer in the Cancer Genome Atlas (TCGA) database was included as a validation cohort. Correlations between these checkpoints, tumor-infiltrating- lymphocytes (TILs), and survival were analyzed. Results and discussion: CTLA4 was detectable in 87.3% of samples, VISTA in 64.7%, PD1 in 56.7%, and PDL1 in 48.1%. PDL1 was the only tested protein associated with an advanced stage (p=0.05). VISTA was associated with PDL1, PD1, and CTLA4 expressions (p=0.005, p=0.001, p=0.008, respectively), consistent with mRNA level analysis from the TCGA database. Univariate analyses showed only VISTA expression (p=0.04) correlated with overall survival (OS). Multivariate analyses showed that VISTA expression (p=0.01) and the coexpression of VISTA+/CTLA4+/PD1+ (p=0.05) were associated with better OS independently of the clinicopathological features. Kaplan-Meier analysis showed that the coexpression of the VISTA+/CTLA4+/PDL1+ and VISTA+/CTLA4+/PD1+ checkpoints on tumor cells (TCs)were associated with OS (p=0.02 and p<0.001; respectively). VISTA+/CTLA4+/PD1+ in TCs and CD4+/CD8+TILs were associated with better 2-yer OS. This correlation may refer to the role of VISTA as a receptor in the TCs and not in the immune cells. Thus, targeting combination therapy blocking VISTA, CTLA4, and PD1 could be a novel and attractive strategy for HGSOC treatment, considering the ambivalent role of VISTA in the HGSOC tumor cells. [ABSTRACT FROM AUTHOR]

Background: VISTA is a well-known immune checkpoint in T cell biology, but its role in innate immunity is less established. Here, we investigated the role of VISTA on anticancer macrophage immunity, with a focus on phagocytosis, macrophage polarization and concomitant T cell activation. Methods: Macrophages, differentiated from VISTA overexpressed THP-1 cells and cord blood CD34+ cell-derived monocytes, were used in phagocytosis assay using B lymphoma target cells opsonized with Rituximab. PBMC-derived macrophages were used to assess the correlation between phagocytosis and VISTA expression. qRT-PCR, flow cytometry, and enzyme-linked immunosorbent assay were performed to analyze the impact of VISTA on other checkpoints and M1/M2-like macrophage biology. Additionally, flow cytometry was used to assess the frequency of CD14+ monocytes expressing VISTA in PBMCs from 65 lymphoma patients and 37 healthy donors. Results: Ectopic expression of VISTA in the monocytic model cell line THP-1 or in primary monocytes triggered differentiation towards the macrophage lineage, with a marked increase in M2-like macrophage-related gene expression and decrease in M1-like macrophage-related gene expression. VISTA expression in THP-1 and monocyte-derived macrophages strongly downregulated expression of SIRPα, a prominent 'don't eat me' signal, and augmented phagocytic activity of macrophages against cancer cells. Intriguingly, expression of VISTA's extracellular domain alone sufficed to trigger phagocytosis in ∼ 50% of cell lines, with those cell lines also directly binding to recombinant human VISTA, indicating ligand-dependent and -independent mechanisms. Endogenous VISTA expression was predominantly higher in M2-like macrophages compared to M0- or M1-like macrophages, with a positive correlation observed between VISTA expression in M2c macrophages and their phagocytic activity. VISTA-expressing macrophages demonstrated a unique cytokine profile, characterized by reduced IL-1β and elevated IL-10 secretion. Furthermore, VISTA interacted with MHC-I and downregulated its surface expression, leading to diminished T cell activation. Notably, VISTA surface expression was identified in monocytes from all lymphoma patients but was less prevalent in healthy donors. Conclusions: Collectively, VISTA expression associates with and drives M2-like activation of macrophages with a high phagocytic capacity yet a decrease in antigen presentation capability to T cells. Therefore, VISTA is a negative immune checkpoint regulator in macrophage-mediated immune suppression. [ABSTRACT FROM AUTHOR]

Breaking the poor permeability of immune checkpoint inhibitors (ICIs) caused by the stromal barrier and reversing the immunosuppressive microenvironment are significant challenges in pancreatic cancer immunotherapy. In this study, we synthesized core-shell Fe3O4@TiO2 nanoparticles to act as carriers for loading VISTA monoclonal antibodies to form Fe3O4@TiO2@VISTAmAb (FTV). The nanoparticles are designed to target the overexpressed ICIs VISTA in pancreatic cancer, aiming to improve magnetic resonance imaging-guided sonodynamic therapy (SDT)-facilitated immunotherapy. Laser confocal microscopy and flow cytometry results demonstrate that FTV nanoparticles are specifically recognized and phagocytosed by Panc-2 cells. In vivo experiments reveal that ultrasound-triggered TiO2 SDT can induce tumor immunogenic cell death (ICD) and recruit T-cell infiltration within the tumor microenvironment by releasing damage-associated molecular patterns (DAMPs). Furthermore, ultrasound loosens the dense fibrous stroma surrounding the pancreatic tumor and increases vascular density, facilitating immune therapeutic efficiency. In summary, our study demonstrates that FTV nanoparticles hold great promise for synergistic SDT and immunotherapy in pancreatic cancer.

V-domain Ig suppressor of T cell activation (VISTA), encoded by the human VSIR gene, is a B7 family checkpoint homologous to the programmed death-Ligand 1 sequence. In gynecologic malignancies, VISTA is abnormally expressed and regulates the tumor immune microenvironment, causing a high upregulation of VISTA expression in T-cells and myeloid cells in the tumor microenvironment and promoting tumor proliferation, progression, and immune tolerance. Here, we review the research progress of VISTA in ovarian, cervical, and endometrial cancers through its structure and immunomodulatory mechanism. The comprehensive study of VISTA is expected to improve the current problem of poor immunotherapeutic effects and provide new ideas for immune therapy in patients with gynecologic tumors.

Objective(s): Exhausted CD8+ T-cells over-express immune checkpoint receptors (ICRs), which interact with their ligands on malignant cells. However, some ICRs have been reported to be expressed on both T-cells and tumor cells, including V-domain immunoglobulin suppressor of T cell activation (VISTA), Galectin-9, and T-cell immunoglobulin mucin-3 (TIM-3). We aimed to evaluate the mRNA expression of VISTA, Galectin-9, and TIM-3 on CD8+ T-cells and leukemic cells in B-cell acute lymphoblastic leukemia (B-ALL).Materials and Methods: Samples were obtained from 26 untreated B-ALL patients and 25 control subjects. CD8+ T-cells were isolated using Magnetic Activated Cell Sorting (MACS). Relative gene expression was then evaluated by qRT-PCR with specific primers for VISTA, Galectin-9, and TIM-3. Also, the mRNA expression profile and clinical data of 154 B-ALL patients were obtained from the TARGET.Results: mRNA expression of Galectin-9 on CD8+ T-cells in B-ALL patients was significantly lower than those in the control group (P=0.043), while VISTA expression was not significantly different between the two study groups (P=0.259). Besides, TIM-3 expression was significantly higher in B-ALL patients than in the control group (P

Developing new therapeutic agents for cancer immunotherapy is highly demanding due to the low response ratio of PD-1/PD-L1 blockade in cancer patients. Here, we discovered that the novel immune checkpoint VISTA is highly expressed on a variety of tumor-infiltrating immune cells, especially myeloid derived suppressor cells (MDSCs) and CD8+ T cells. Then, peptide C1 with binding affinity to VISTA was developed by phage displayed bio-panning technique, and its mutant peptide VS3 was obtained by molecular docking based mutation. Peptide VS3 could bind VISTA with high affinity and block its interaction with ligand PSGL-1 under acidic condition, and elicit anti-tumor activity in vivo. The peptide DVS3-Pal was further designed by d-amino acid substitution and fatty acid modification, which exhibited strong proteolytic stability and significant anti-tumor activity through enhancing CD8+ T cell function and decreasing MDSCs infiltration. This is the first study to develop peptides to block VISTA/PSGL-1 interaction, which could act as promising candidates for cancer immunotherapy.

Abstract V-domain immunoglobulin suppressor of T cell activation (VISTA) is a novel negative checkpoint receptor (NCR) primarily involved in maintaining immune tolerance. It has a role in the pathogenesis of autoimmune disorders and cancer and has shown promising results as a therapeutic target. However, there is still some ambiguity regarding the ligands of VISTA and their interactions with each other. While V-Set and Immunoglobulin domain containing 3 (VSIG-3) and P-selectin glycoprotein ligand-1(PSGL-1) have been extensively studied as ligands for VISTA, the others have received less attention. It seems that investigating VISTA ligands, reviewing their functions and roles, as well as outcomes related to their interactions, may allow an understanding of their full functionality and effects within the cell or the microenvironment. It could also help discover alternative approaches to target the VISTA pathway without causing related side effects. In this regard, we summarize current evidence about VISTA, its related ligands, their interactions and effects, as well as their preclinical and clinical targeting agents.

Root exposure generates major concerns regarding aesthetics and other problems like hypersensitivity and root caries. Gingival recession has traditionally been treated by periodontal plastic surgery, often using soft tissue grafts to fill the defect with excellent clinical results. Advancements in root coverage procedures in the aesthetic zone have led to increasing the ability of clinicians to harness a treatment modality that delivers better outcomes with less surgical morbidity. Collagen membrane is most commonly used for guided tissue regeneration (GTR). On the other hand, platelet-rich fibrin (PRF) has gained popularity due to its simple method of acquisition, low cost and the presence of growth factors. Therefore, this case report describes the treatment of a 38-year-old patient with bilateral multiple Miller’s class I recession defects extending from central incisors to canines by using the vestibular incision subperiosteal tunnel access (VISTA) with PRF and collagen membrane. Clinical parameters such as recession height (RH) and width of keratinised gingiva (WKG) were measured at 6-month and 1-year follow up intervals. The 6-month follow-up revealed optimum root coverage with excellent outcomes for both sites, with an increase in the width of keratinised gingiva and a decrease in the recession height, and less discomfort in the site treated with a PRF membrane. These clinical parameters were maintained at the 1-year follow up. The increase in the width of keratinised gingiva and the decrease in the recession height in both groups and the patient compliance due to this minimally invasive procedure suggests its potential use when aesthetics and patient comfort are of paramount concern.

IntroductionImmunotherapy by blocking immune checkpoints programmed death/ligand (PD1/PDL1) and cytotoxic T-lymphocyte-associated protein 4(CTLA4) has emerged as new therapeutic targets in cancer. However, their efficacy has been limited due to resistance. A new- checkpoint V-domain Ig-containing suppressor of T cell activation (VISTA) has appeared, but the use of its inhibition effect in combination with antibodies targeting PDL1/PD1and CTLA4 has not been reported in ovarian cancer.MethodsIn this study, we investigated the expressions of VISTA, CTLA4, and PDL1 using immunohistochemistry (IHC)on 135 Formalin-Fixed Paraffin-Embedded (FFPE)tissue samples of High-grade serous carcinoma (HGSOC). VISTA, CTLA4, PDL1, PD1, CD8, CD4, and FOXP3 mRNA extracted from 429 patients with ovarian cancer in the Cancer Genome Atlas (TCGA) database was included as a validation cohort. Correlations between these checkpoints, tumor-infiltrating- lymphocytes (TILs), and survival were analyzed.Results and discussionCTLA4 was detectable in 87.3% of samples, VISTA in 64.7%, PD1 in 56.7%, and PDL1 in 48.1%. PDL1 was the only tested protein associated with an advanced stage (p=0.05). VISTA was associated with PDL1, PD1, and CTLA4 expressions (p=0.005, p=0.001, p=0.008, respectively), consistent with mRNA level analysis from the TCGA database. Univariate analyses showed only VISTA expression (p=0.04) correlated with overall survival (OS). Multivariate analyses showed that VISTA expression (p=0.01) and the coexpression of VISTA+/CTLA4+/PD1+ (p=0.05) were associated with better OS independently of the clinicopathological features. Kaplan-Meier analysis showed that the coexpression of the VISTA+/CTLA4+/PDL1+ and VISTA+/CTLA4+/PD1+ checkpoints on tumor cells (TCs)were associated with OS (p=0.02 and p

Introduction: Pancreatic cancer is a truculent disease with limited treatment options and a grim prognosis. Immunotherapy has shown promise in treating various types of cancer, but its effectiveness in pancreatic cancer has been lacking. As a result, it is crucial to identify markers associated with immunological pathways in order to improve the treatment outcomes for this deadly cancer. The purpose of this study was to investigate the diagnostic and prognostic significance of three markers, CD8, CD68, and VISTA, in pancreatic ductal adenocarcinoma (PDAC), the most common subtype of pancreatic cancer. Methods: We analyzed gene expression data from Gene Expression Omnibus (GEO) database using bioinformatics tools. We also utilized the STRING online tool and Funrich software to study the protein-protein interactions and transcription factors associated with CD8, CD68, and VISTA. In addition, tissue microarray (TMA) and immunohistochemistry (IHC) staining were performed on 228 samples of PDAC tissue and 10 samples of normal pancreatic tissue to assess the expression levels of the markers. We then correlated these expression levels with the clinicopathological characteristics of the patients and evaluated their survival rates. Results: The analysis of the GEO data revealed slightly elevated levels of VISTA in PDAC samples compared to normal tissues. However, there was a significant increase in CD68 expression and a notable reduction in CD8A expression in pancreatic cancer. Further investigation identified potential protein-protein interactions and transcription factors associated with these markers. The IHC staining of PDAC tissue samples showed an increased expression of VISTA, CD68, and CD8A in pancreatic cancer tissues. Moreover, we found correlations between the expression levels of these markers and certain clinicopathological features of the patients. Additionally, the survival analysis revealed that high expression of CD8 was associated with better disease-specific survival and progression-free survival in PDAC patients. Conclusion: These findings highlight the potential of CD8, CD68, and VISTA as diagnostic and prognostic indicators in PDAC. [ABSTRACT FROM AUTHOR]

Background: Immune checkpoint therapies have led to significant breakthroughs in cancer patient treatment in recent years. However, their efficiency is variable, and resistance to immunotherapies is common. VISTA is an immune-suppressive checkpoint inhibitor of T cell response belonging to the B7 family and a promising novel therapeutic target. VISTA is expressed in the immuno-suppressive tumor microenvironment, primarily by myeloid lineage cells, and its genetic knockout or antibody blockade restores an efficient antitumor immune response. Methods: Fully human monoclonal antibodies directed against VISTA were produced after immunizing humanized Trianni mice and sorting and sequencing natively-linked B cell scFv repertoires. Anti-VISTA antibodies were evaluated for specificity, cross-reactivity, monocyte and T cell activation, Fceffector functions, and antitumor efficacy using in vitro and in vivo models to select the KVA12123 antibody lead candidate. The pharmacokinetics and safety profiles of KVA12123 were evaluated in cynomolgus monkeys. Results: Here, we report the development of a clinical candidate anti-VISTA monoclonal antibody, KVA12123. KVA12123 showed high affinity binding to VISTA through a unique epitope distinct from other clinical-stage anti-VISTA monoclonal antibodies. This clinical candidate demonstrated high specificity against VISTA with no cross-reactivity detected against other members of the B7 family. KVA12123 blocked VISTA binding to its binding partners. KVA12123 induced T cell activation and demonstrated NK-mediated monocyte activation. KVA12123 treatment mediated strong single-agent antitumor activity in several syngeneic tumor models and showed enhanced efficacy in combination with anti-PD-1 treatment. This clinical candidate was engineered to improve its pharmacokinetic characteristics and reduce Fc-effector functions. It was welltolerated in preclinical toxicology studies in cynomolgus monkeys, where hematology, clinical chemistry evaluations, and clinical observations revealed no indicators of toxicity. No cytokines associated with cytokine release syndrome were elevated. Conclusion: These results establish that KVA12123 is a promising drug candidate with a distinct but complementary mechanism of action of the first generation of immune checkpoint inhibitors. This antibody is currently evaluated alone and in combination with pembrolizumab in a Phase 1/2 open-label clinical trial in patients with advanced solid tumors. [ABSTRACT FROM AUTHOR]

Background and aims: In gastric cancer, the response rate of programmed cell death protein‐1 (PD‐1) inhibitor is far from satisfactory, indicating additional nonredundant pathways might hamper antitumour immunity. V‐domain immunoglobulin suppressor of T‐cell activation (VISTA) has been reported in several malignancies as a novel immune‐checkpoint. Nevertheless, the role of VISTA in gastric cancer still remains obscure. Our purpose is to explore the clinical significance and potential mechanism of VISTA in affecting gastric cancer patients' survival and immunotherapeutic responsiveness. Methods: Our study recruited eight independent cohorts with a total of 1403 gastric cancer patients. Immunohistochemistry, multiplex immunofluorescence, flow cytometry or intracellular flow cytometry, quantitative polymerase chain reaction, western blotting, fluorescence‐activated cell sorting, magnetic‐activated cell sorting, smart‐seq2, in vitro cell co‐culture and ex vivo tumour inhibition assays were applied to investigate the clinical significance and potential mechanism of VISTA in gastric cancer. Results: VISTA was predominantly expressed on tumour‐associated macrophages (TAMs), and indicated poor clinical outcomes and inferior immunotherapeutic responsiveness. VISTA+ TAMs showed a mixed phenotype. Co‐culture of TAMs and CD8+ T cells indicated that VISTA+ TAMs attenuated effective function of CD8+ T cells. Blockade of VISTA reprogrammed TAMs to a proinflammatory phenotype, reactivated CD8+ T cells and promoted apoptosis of tumour cells. Moreover, blockade of VISTA could also enhance the efficacy of PD‐1 inhibitor, suggesting that blockade of VISTA might synergise with PD‐1 inhibitor in gastric cancer. Conclusions: Our data revealed that VISTA was an immune‐checkpoint associated with immunotherapeutic resistance. Blockade of VISTA reprogrammed TAMs, promoted T‐cell‐mediated antitumour immunity, and enhanced efficacy of PD‐1 inhibitor, which might have implications in the treatment of gastric cancer. [ABSTRACT FROM AUTHOR]

Immune checkpoints (ICPs) serve as regulatory switches on immune-competent cells. Soluble ICPs consist of fragments derived from ICP molecules typically located on cell membranes. Research has demonstrated that they perform similar functions to their membrane-bound counterparts but are directly present in the bloodstream. Effective control of the maternal immune system is vital for a successful pregnancy due to genetic differences between the mother and fetus. Abnormalities in the immune response are widely acknowledged as the primary cause of spontaneous abortions. In our research, we introduce a novel approach to understanding the immune-mediated mechanisms underlying recurrent miscarriages and explore new possibilities for diagnosing and preventing pregnancy loss. The female participants in the study were divided into three groups: RSA (recurrent spontaneous abortion), pregnant, and non-pregnant women. The analysis of soluble forms of immune checkpoints and their ligands in the serum of the study groups was conducted using the Luminex method Statistically significant differences in the concentrations of (ICPs) were observed between physiological pregnancies and the RSA group. Among patients with RSA, we noted reduced concentrations of sGalectin-9, sTIM-3, and sCD155, along with elevated concentrations of LAG-3, sCD80, and sCD86 ICPs, in comparison to physiological pregnancies. Our study indicates that sGalectin-9, TIM-3, sLAG-3, sCD80, sCD86, sVISTA, sNectin-2, and sCD155 could potentially serve as biological markers of a healthy, physiological pregnancy. These findings suggest that changes in the concentrations of soluble immune checkpoints may have the potential to act as markers for early pregnancy loss. [ABSTRACT FROM AUTHOR]

Background.: Gingival recession (GR) has become one of the most common concerns in oral mucosal diseases. It causes discomfort such as root hypersensitivity, root caries, and aesthetic problems, leading to the development of various surgical techniques to address GRs. This study compared the non-advanced tunnel and m-VISTA techniques in treating multiple GRs. Methods.: A literature search related to the efficiency of non-advanced tunnel and m-VISTA techniques was conducted in MEDLINE (PubMed), EMBASE (ScienceDirect), Cochrane Central Register of Controlled Trials (Cochrane Library), Springer Link, and Google Scholar. Randomized controlled trials (RCTs) reporting periodontal parameters published in the recent four years (2019–2023) were included and assessed for the risk of bias. All in vitro, animal, pilot studies, case reports, and case series were excluded. Results.: Five RCTs were included with 195 cases of GRs. Comparing the two techniques revealed a significant increase in keratinized tissue width (KTW) from baseline to 6 months (-1.4 mm), in clinical attachment level (CAL) (-2.65 mm), and in recession depth (-2.7 mm) for the tunnel technique. On the other hand, a significant increase in GR width (-2.26 mm) was found in the m-VISTA group. Finally, there were no significant differences in probing depths. Conclusion.: Both techniques were effective in root coverage and may be valuable for treating multiple GRs. [ABSTRACT FROM AUTHOR]

Objective(s): Exhausted CD8+ T-cells over-express immune checkpoint receptors (ICRs), which interact with their ligands on malignant cells. However, some ICRs have been reported to be expressed on both T-cells and tumor cells, including V-domain immunoglobulin suppressor of T cell activation (VISTA), Galectin-9, and T-cell immunoglobulin mucin-3 (TIM-3). We aimed to evaluate the mRNA expression of VISTA, Galectin-9, and TIM-3 on CD8+ T-cells and leukemic cells in B-cell acute lymphoblastic leukemia (B-ALL). Materials and Methods: Samples were obtained from 26 untreated B-ALL patients and 25 control subjects. CD8+ T-cells were isolated using Magnetic Activated Cell Sorting (MACS). Relative gene expression was then evaluated by qRT-PCR with specific primers for VISTA, Galectin-9, and TIM-3. Also, the mRNA expression profile and clinical data of 154 B-ALL patients were obtained from the TARGET. Results: mRNA expression of Galectin-9 on CD8+ T-cells in B-ALL patients was significantly lower than those in the control group (P=0.043), while VISTA expression was not significantly different between the two study groups (P=0.259). Besides, TIM-3 expression was significantly higher in B-ALL patients than in the control group (P<0.001). Also, data obtained from TARGET showed that the relapse incidence was not significantly different between patients with high and low expression of Galectin-9 and TIM-3 in leukemic cells (P=0.360 and P=0.655, respectively). Conclusion: Collectively, gene expression results suggest an important role for TIM-3, but not VISTA and Galectin-9, in B-ALL and it seems that TIM-3 could be a candidate for immune checkpoint therapy. [ABSTRACT FROM AUTHOR]

Objectives: This study investigated the efficacy of Vestibular Incision Subperiosteal Tunnel Access (VISTA) compared to other methods for treating multiple adjacent gingival recessions (MAGRs) through a systematic review and meta-analysis. Materials and methods: A systematic literature search was performed through June 2023, to identify clinical trials investigating VISTA for root coverage on MAGRs. A meta-analysis with meta-regression model was employed on the primary outcomes of mean and complete root coverages (MRC, CRC), comparing VISTA with other techniques. Clinical efficacy of various graft materials was assessed. Results: Fourteen studies were included, 8 of which met the criteria for quantitative assessment. The cumulative MRC (88.15% ± 20.79%) and CRC (67.85% ± 21.72%) of VISTA were significantly higher compared to the tunneling technique (SMD = 0.83 (95% CI [0.36, 1.30], p < 0.01). The baseline recession depth showed a negative correlation with CRC, whereas baseline keratinized gingiva width exhibited a positive correlation with this outcome. Conclusions: The VISTA technique, particularly with acellular dermal matrix (ADM) or connective tissue graft (CTG) materials, offers superior outcomes compared to the tunneling technique. The capacity of platelet-rich fibrin (PRF) to substitute for connective tissue graft (CTG) in VISTA-root coverage was noteworthy, provided there is adequate keratinized tissue width. Clinical relevance: VISTA in concert with acellular dermal matrix or CTG resulted in improved root coverage, surpassing the outcomes achieved through tunneling. PRF emerged as a viable alternative to CTG, when used in conjunction with VISTA, demonstrating comparable mean root coverage. This is particularly evident in situations where sufficient keratinized gingiva is available and when patient comfort is taken into consideration. [ABSTRACT FROM AUTHOR]

V-domain immunoglobulin suppressor of T-cell activation (VISTA), an important negative checkpoint protein, participates in immunoregulation. Systemic lupus erythematosus (SLE) is an autoimmune disease in which patients exhibit high levels of autoantibodies and multi-organ tissue injury, primarily involving the kidney and skin. In wild-type (WT) mice and Vsir-/- mice with pristane-induced lupus-like disease, we found that VISTA deficiency exacerbated the lupus-like disease in mice, possibly through aberrant activation of type I interferon (IFN-I) signaling, CD4+ T cell, and noncanonical nuclear factor-κB (NF-κB) pathway. Surface plasmon resonance results showed that imatinib, an FDA-approved tyrosine kinase inhibitor, may have a high affinity for human VISTA-ECD with a KD value of 0.2009 μM. The biological activities of imatinib and VISTA agonist M351-0056 were studied in monocytes and T cells and in lupus-like disease murine model of chronic graft-versus-host disease (cGVHD) and lupus-prone MRL/lpr mice. VISTA small-molecule agonist reduced the cytokine production of peripheral blood mononuclear cells (PBMCs) and Jurkat cells and inhibited PBMCs proliferation. Moreover, they attenuated the levels of autoantibodies, renal injury, inflammatory cytokines, chemokines, and immune cell expansion in the cGVHD mouse model and MRL/lpr mice. Our findings also demonstrated that VISTA small-molecule agonist ameliorated the development of SLE through improving aberrantly activated IFN-I signaling and noncanonical NF-κB pathway. In conclusion, VISTA has a protective effect on the development and progression of SLE. VISTA agonist M351-0056 and imatinib have been firstly demonstrated to attenuate SLE, suggesting interventions to enhance VISTA function may be effective in treating SLE. [ABSTRACT FROM AUTHOR]

Abstract The immune-related microenvironment of thymic carcinoid has rarely been reported. We analyzed the expression of PD-L1 and VISTA, and the distribution of CD4+ T cells, CD8+ T cells and CD68+ macrophages in the thymic carcinoid by immunohistochemical staining, and showed the correlation between these markers and clinical survival, indicating the potential therapeutic prospects.