{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T21:43:40Z","timestamp":1792014220683,"version":"4.4.0"},"reference-count":126,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2023,6,9]],"date-time":"2023-06-09T00:00:00Z","timestamp":1686268800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>While gastrointestinal tumors remain a multifactorial and prevalent group of malignancies commonly treated surgically in combination with chemotherapy and radiotherapy, advancements regarding immunotherapeutic approaches continue to occur. Entering a new era of immunotherapy focused on overcoming resistance to preceding therapies caused the emergence of new therapeutic strategies. A promising solution surfaces with a V-domain Ig suppressor of T-cell activation (VISTA), a negative regulator of a T-cell function expressed in hematopoietic cells. Due to VISTA\u2019s ability to act as both a ligand and a receptor, several therapeutic approaches can be potentially developed. A broad expression of VISTA was discovered on various tumor-growth-controlling cells, which proved to increase in specific tumor microenvironment (TME) conditions, thus serving as a rationale behind the development of new VISTA-targeting. Nevertheless, VISTA\u2019s ligands and signaling pathways are still not fully understood. The uncertain results of clinical trials suggest the need for future examining inhibitor agents for VISTA and implicating a double immunotherapeutic blockade. However, more research is needed before the breakthrough can be achieved. This review discusses perspectives and novel approaches presented in the current literature. Based on the results of the ongoing studies, VISTA might be considered a potential target in combined therapy, especially for treating gastrointestinal malignancies.<\/jats:p>","DOI":"10.3390\/ijms24129945","type":"journal-article","created":{"date-parts":[[2023,6,9]],"date-time":"2023-06-09T09:54:32Z","timestamp":1686304472000},"page":"9945","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Vista of the Future: Novel Immunotherapy Based on the Human V-Set Immunoregulatory Receptor for Digestive System Tumors"],"prefix":"10.3390","volume":"24","author":[{"given":"Paulina","family":"Chmiel","sequence":"first","affiliation":[{"name":"Department of Surgical Oncology, Medical University of Lublin, Radziwi\u0142\u0142owska 13 St., 20-080 Lublin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katarzyna","family":"G\u0119ca","sequence":"additional","affiliation":[{"name":"Department of Surgical Oncology, Medical University of Lublin, Radziwi\u0142\u0142owska 13 St., 20-080 Lublin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9598-373X","authenticated-orcid":false,"given":"Adam","family":"Michalski","sequence":"additional","affiliation":[{"name":"Department of Surgical Oncology, Medical University of Lublin, Radziwi\u0142\u0142owska 13 St., 20-080 Lublin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martyna","family":"K\u0142osi\u0144ska","sequence":"additional","affiliation":[{"name":"Department of Surgical Oncology, Medical University of Lublin, Radziwi\u0142\u0142owska 13 St., 20-080 Lublin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8943-9401","authenticated-orcid":false,"given":"Agnieszka","family":"Kaczy\u0144ska","sequence":"additional","affiliation":[{"name":"Department of Surgical Oncology, Medical University of Lublin, Radziwi\u0142\u0142owska 13 St., 20-080 Lublin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6455-5636","authenticated-orcid":false,"given":"Wojciech P.","family":"Polkowski","sequence":"additional","affiliation":[{"name":"Department of Surgical Oncology, Medical University of Lublin, Radziwi\u0142\u0142owska 13 St., 20-080 Lublin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zuzanna","family":"Pelc","sequence":"additional","affiliation":[{"name":"Department of Surgical Oncology, Medical University of Lublin, Radziwi\u0142\u0142owska 13 St., 20-080 Lublin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5004-9940","authenticated-orcid":false,"given":"Magdalena","family":"Sk\u00f3rzewska","sequence":"additional","affiliation":[{"name":"Department of Surgical Oncology, Medical University of Lublin, Radziwi\u0142\u0142owska 13 St., 20-080 Lublin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,6,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"454","DOI":"10.1016\/j.ccell.2020.07.013","article-title":"Identifying and Targeting Human Tumor Antigens for T Cell-Based Immunotherapy of Solid Tumors","volume":"38","author":"Leko","year":"2020","journal-title":"Cancer Cell"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1016\/j.ccell.2015.03.001","article-title":"Immune Checkpoint Blockade: A Common Denominator Approach to Cancer Therapy","volume":"27","author":"Topalian","year":"2015","journal-title":"Cancer Cell"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1002\/cjp2.193","article-title":"Relationship between Immune Checkpoint Proteins, Tumour Microenvironment Characteristics, and Prognosis in Primary Operable Colorectal Cancer","volume":"7","author":"Grant","year":"2021","journal-title":"J. Pathol. Clin. Res."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1313","DOI":"10.1002\/jcp.27172","article-title":"PD-1\/PD-L1 Immune Checkpoint: Potential Target for Cancer Therapy","volume":"234","author":"Dermani","year":"2019","journal-title":"J. Cell Physiol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1069","DOI":"10.1158\/2159-8290.CD-18-0367","article-title":"Fundamental Mechanisms of Immune Checkpoint Blockade Therapy","volume":"8","author":"Wei","year":"2018","journal-title":"Cancer Discov."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1186\/s12943-019-1091-2","article-title":"Novel Immune Checkpoint Targets: Moving beyond PD-1 and CTLA-4","volume":"18","author":"Qin","year":"2019","journal-title":"Mol. Cancer"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"e1293215","DOI":"10.1080\/2162402X.2017.1293215","article-title":"The Novel Negative Checkpoint Regulator VISTA Is Expressed in Gastric Carcinoma and Associated with PD-L1\/PD-1: A Future Perspective for a Combined Gastric Cancer Therapy?","volume":"6","author":"Behrens","year":"2017","journal-title":"Oncoimmunology"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"e1581546","DOI":"10.1080\/2162402X.2019.1581546","article-title":"The Expression of the Immune Checkpoint Regulator VISTA Correlates with Improved Overall Survival in PT1\/2 Tumor Stages in Esophageal Adenocarcinoma","volume":"8","author":"Loeser","year":"2019","journal-title":"Oncoimmunology"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"474","DOI":"10.21037\/jgo.2017.05.01","article-title":"Immunotherapy in Gastrointestinal Cancers","volume":"8","author":"Grierson","year":"2017","journal-title":"J. Gastrointest. Oncol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"665","DOI":"10.3747\/co.26.5193","article-title":"Eastern Canadian Gastrointestinal Cancer Consensus Conference 2018","volume":"26","author":"Hyde","year":"2019","journal-title":"Curr. Oncol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"689","DOI":"10.1136\/jim-2020-001654","article-title":"Current Immunotherapy in Gastrointestinal Malignancies A Review","volume":"69","author":"Dahiya","year":"2021","journal-title":"J. Investig. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"102142","DOI":"10.1016\/j.ctrv.2020.102142","article-title":"Recent Advances in Neoadjuvant Immunotherapy for Urothelial Bladder Cancer: What to Expect in the near Future","volume":"93","author":"Bote","year":"2021","journal-title":"Cancer Treat. Rev."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"3753","DOI":"10.1158\/1078-0432.CCR-18-4070","article-title":"FDA Approval Summary: Pembrolizumab for the Treatment of Microsatellite Instability-High Solid Tumors","volume":"25","author":"Marcus","year":"2019","journal-title":"Clin. Cancer Res."},{"key":"ref_14","first-page":"5123","article-title":"Current Progress and Future Perspectives of Neoadjuvant Anti-PD-1\/PD-L1 Therapy for Colorectal Cancer","volume":"13","author":"Yang","year":"2022","journal-title":"Front. Immunol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"491","DOI":"10.2217\/fon-2020-0737","article-title":"First-Line Pembrolizumab\/Placebo plus Trastuzumab and Chemotherapy in HER2-Positive Advanced Gastric Cancer: KEYNOTE-811","volume":"17","author":"Chung","year":"2021","journal-title":"Future Oncol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1057","DOI":"10.2217\/fon-2018-0609","article-title":"KEYNOTE-590: Phase III Study of First-Line Chemotherapy with or without Pembrolizumab for Advanced Esophageal Cancer","volume":"15","author":"Kato","year":"2019","journal-title":"Future Oncol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2492","DOI":"10.1016\/S0140-6736(17)31046-2","article-title":"Nivolumab in Patients with Advanced Hepatocellular Carcinoma (CheckMate 040): An Open-Label, Non-Comparative, Phase 1\/2 Dose Escalation and Expansion Trial","volume":"389","author":"Sangro","year":"2017","journal-title":"Lancet"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1159\/000507798","article-title":"Immunotherapy in Gastrointestinal Cancers","volume":"36","author":"Ettrich","year":"2020","journal-title":"Visc. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"109821","DOI":"10.1016\/j.biopha.2020.109821","article-title":"Cancer Immunotherapy: Pros, Cons and Beyond","volume":"124","author":"Tan","year":"2020","journal-title":"Biomed. Pharmacother."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1016\/j.ccell.2020.03.017","article-title":"Acquired Resistance to Immune Checkpoint Inhibitors","volume":"37","author":"Schoenfeld","year":"2020","journal-title":"Cancer Cell"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1537","DOI":"10.4049\/jimmunol.1100660","article-title":"Cutting Edge: A Monoclonal Antibody Specific for the Programmed Death-1 Homolog Prevents Graft-versus-Host Disease in Mouse Models","volume":"187","author":"Flies","year":"2011","journal-title":"J. Immunol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1084\/jem.20100619","article-title":"VISTA, a Novel Mouse Ig Superfamily Ligand That Negatively Regulates T Cell Responses","volume":"208","author":"Wang","year":"2011","journal-title":"J. Exp. Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1924","DOI":"10.1158\/0008-5472.CAN-13-1504","article-title":"VISTA Is an Immune Checkpoint Molecule for Human T Cells","volume":"74","author":"Lines","year":"2014","journal-title":"Cancer Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2509","DOI":"10.1016\/j.celrep.2019.07.073","article-title":"Structure and Functional Binding Epitope of V-Domain Ig Suppressor of T Cell Activation","volume":"28","author":"Mehta","year":"2019","journal-title":"Cell Rep."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1966","DOI":"10.1172\/JCI74589","article-title":"Coinhibitory Receptor PD-1H Preferentially Suppresses CD4+ T Cell\u2013Mediated Immunity","volume":"124","author":"Flies","year":"2014","journal-title":"J. Clin. Investig."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1111\/cei.13415","article-title":"VISTA: Coming of Age as a Multi-Lineage Immune Checkpoint","volume":"200","author":"ElTanbouly","year":"2020","journal-title":"Clin. Exp. Immunol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"5031","DOI":"10.1073\/pnas.87.13.5031","article-title":"T-Cell Antigen CD28 Mediates Adhesion with B Cells by Interacting with Activation Antigen B7\/BB-1","volume":"87","author":"Linsley","year":"1990","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"e1469594","DOI":"10.1080\/2162402X.2018.1469594","article-title":"VISTA Is Highly Expressed on MDSCs and Mediates an Inhibition of T Cell Response in Patients with AML","volume":"7","author":"Wang","year":"2018","journal-title":"Oncoimmunology"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"766","DOI":"10.3389\/fimmu.2023.1086102","article-title":"VISTA Expression and Patient Selection for Immune-Based Anticancer Therapy","volume":"14","author":"Martin","year":"2023","journal-title":"Front. Immunol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1648","DOI":"10.1073\/pnas.1908711117","article-title":"Structural Insight into T Cell Coinhibition by PD-1H (VISTA)","volume":"117","author":"Slater","year":"2020","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1002\/pro.3943","article-title":"UCSF ChimeraX: Structure Visualization for Researchers, Educators, and Developers","volume":"30","author":"Pettersen","year":"2021","journal-title":"Protein Sci."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1093\/nar\/28.1.235","article-title":"The Protein Data Bank","volume":"28","author":"Berman","year":"2000","journal-title":"Nucleic Acids Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1111\/imm.13001","article-title":"VSIG-3 as a Ligand of VISTA Inhibits Human T-Cell Function","volume":"156","author":"Wang","year":"2019","journal-title":"Immunology"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1038\/s41586-019-1674-5","article-title":"VISTA Is an Acidic PH-Selective Ligand for PSGL-1","volume":"574","author":"Johnston","year":"2019","journal-title":"Nature"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"580557","DOI":"10.3389\/fimmu.2020.580557","article-title":"Ligand-Receptor Interactions of Galectin-9 and VISTA Suppress Human T Lymphocyte Cytotoxic Activity","volume":"11","author":"Yasinska","year":"2020","journal-title":"Front. Immunol."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Bharaj, P., Chahar, H.S., Alozie, O.K., Rodarte, L., Bansal, A., Goepfert, P.A., Dwivedi, A., Manjunath, N., and Shankar, P. (2014). Characterization of Programmed Death-1 Homologue-1 (PD-1H) Expression and Function in Normal and HIV Infected Individuals. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0109103"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1415","DOI":"10.1007\/s00109-020-01968-x","article-title":"Exploring the VISTA of Microglia: Immune Checkpoints in CNS Inflammation","volume":"98","author":"Borggrewe","year":"1968","journal-title":"J. Mol. Med."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2645","DOI":"10.1002\/glia.23517","article-title":"VISTA Expression by Microglia Decreases during Inflammation and Is Differentially Regulated in CNS Diseases","volume":"66","author":"Borggrewe","year":"2018","journal-title":"Glia"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1485","DOI":"10.1038\/s41598-017-01411-1","article-title":"Immune-Checkpoint Protein VISTA Critically Regulates the IL-23\/IL-17 Inflammatory Axis","volume":"7","author":"Li","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1933","DOI":"10.1158\/0008-5472.CAN-13-1506","article-title":"VISTA Regulates the Development of Protective Antitumor Immunity","volume":"74","author":"Chen","year":"2014","journal-title":"Cancer Res."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1666","DOI":"10.1038\/modpathol.2017.89","article-title":"Negative Immune Checkpoint Regulation by VISTA: A Mechanism of Acquired Resistance to Anti-PD-1 Therapy in Metastatic Melanoma Patients","volume":"30","author":"Kakavand","year":"2017","journal-title":"Mod. Pathol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1113","DOI":"10.1007\/s00262-018-2169-1","article-title":"VISTA Expression on Tumor-Infiltrating Inflammatory Cells in Primary Cutaneous Melanoma Correlates with Poor Disease-Specific Survival","volume":"67","author":"Kuklinski","year":"2018","journal-title":"Cancer Immunol. Immunother."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1685","DOI":"10.1007\/s00262-018-2227-8","article-title":"Expression of the Inhibitory B7 Family Molecule VISTA in Human Colorectal Carcinoma Tumors","volume":"67","author":"Xie","year":"2018","journal-title":"Cancer Immunol. Immunother."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1548","DOI":"10.1158\/2159-8290.CD-18-0804","article-title":"Integrative Molecular Characterization of Malignant Pleural Mesothelioma","volume":"8","author":"Hmeljak","year":"2018","journal-title":"Cancer Discov."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1038\/s41379-019-0364-z","article-title":"V-Domain Ig-Containing Suppressor of T-Cell Activation (VISTA), a Potentially Targetable Immune Checkpoint Molecule, Is Highly Expressed in Epithelioid Malignant Pleural Mesothelioma","volume":"33","author":"Muller","year":"2020","journal-title":"Mod. Pathol."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Zhang, M., Pang, H.-J., Zhao, W., Li, Y.-F., Yan, L.-X., Dong, Z.-Y., and He, X.-F. (2018). VISTA Expression Associated with CD8 Confers a Favorable Immune Microenvironment and Better Overall Survival in Hepatocellular Carcinoma. BMC Cancer, 18.","DOI":"10.1186\/s12885-018-4435-1"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1692","DOI":"10.1073\/pnas.1811067116","article-title":"Comparison of Immune Infiltrates in Melanoma and Pancreatic Cancer Highlights VISTA as a Potential Target in Pancreatic Cancer","volume":"116","author":"Blando","year":"2019","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1111\/imr.12525","article-title":"Immunoregulatory Functions of VISTA","volume":"276","author":"Nowak","year":"2017","journal-title":"Immunol. Rev."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1007\/s00262-017-1968-0","article-title":"Expression of VISTA Correlated with Immunosuppression and Synergized with CD8 to Predict Survival in Human Oral Squamous Cell Carcinoma","volume":"66","author":"Wu","year":"2017","journal-title":"Cancer Immunol. Immunother."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"858","DOI":"10.1016\/j.eururo.2017.01.021","article-title":"A Functional Genetic Screen Identifies the Phosphoinositide 3-Kinase Pathway as a Determinant of Resistance to Fibroblast Growth Factor Receptor Inhibitors in FGFR Mutant Urothelial Cell Carcinoma","volume":"71","author":"Wang","year":"2017","journal-title":"Eur. Urol."},{"key":"ref_51","first-page":"5194","article-title":"Investigation of PD-1H in DEN-Induced Mouse Liver Cancer Model","volume":"22","author":"Lei","year":"2018","journal-title":"Eur. Rev. Med. Pharmacol. Sci."},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Pansy, K., Uhl, B., Krstic, J., Szmyra, M., Fechter, K., Santiso, A., Th\u00fcminger, L., Greinix, H., Kargl, J., and Prochazka, K. (2021). Immune Regulatory Processes of the Tumor Microenvironment under Malignant Conditions. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms222413311"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/S0065-2776(06)90002-9","article-title":"Mechanisms of Immune Evasion by Tumors","volume":"90","author":"Drake","year":"2006","journal-title":"Adv. Immunol."},{"key":"ref_54","first-page":"1","article-title":"Macrophages in Immunoregulation and Therapeutics","volume":"8","author":"Chen","year":"2023","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"2909","DOI":"10.3389\/fimmu.2018.02909","article-title":"Immunomodulation of the Tumor Microenvironment: Turn Foe into Friend","volume":"9","author":"Locy","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"2060","DOI":"10.1126\/science.1072615","article-title":"A Role for CD40 Expression on CD8+ T Cells in the Generation of CD8+ T Cell Memory","volume":"297","author":"Bourgeois","year":"2002","journal-title":"Science"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"3059","DOI":"10.3389\/fimmu.2018.03059","article-title":"Dendritic Cells and CD8 T Cell Immunity in Tumor Microenvironment","volume":"9","author":"Fu","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1158\/2159-8290.CD-20-0655","article-title":"Tumor-Infiltrating Natural Killer Cells","volume":"11","author":"Greppi","year":"2021","journal-title":"Cancer Discov."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1853","DOI":"10.1016\/j.celrep.2017.10.090","article-title":"Reciprocal Expression of IL-35 and IL-10 Defines Two Distinct Effector Treg Subsets That Are Required for Maintenance of Immune Tolerance","volume":"21","author":"Wei","year":"2017","journal-title":"Cell Rep."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"eaak9702","DOI":"10.1126\/scisignal.aak9702","article-title":"Blockade of Surface-Bound TGF-\u03b2 on Regulatory T Cells Abrogates Suppression of Effector T Cell Function in the Tumor Microenvironment","volume":"10","author":"Budhu","year":"2017","journal-title":"Sci. Signal."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1116","DOI":"10.1016\/j.immuni.2015.05.023","article-title":"Quiescence of Memory CD8+ T Cells Is Mediated by Regulatory T Cells through Inhibitory Receptor CTLA-4","volume":"42","author":"Kalia","year":"2015","journal-title":"Immunity"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"852","DOI":"10.1038\/nri3108","article-title":"The Emerging Role of CTLA4 as a Cell-Extrinsic Regulator of T Cell Responses","volume":"11","author":"Walker","year":"2011","journal-title":"Nat. Rev. Immunol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1562","DOI":"10.1158\/1078-0432.CCR-17-2542","article-title":"Spatially Resolved and Quantitative Analysis of VISTA\/PD-1H as a Novel Immunotherapy Target in Human Non-Small Cell Lung Cancer","volume":"24","author":"Yu","year":"2018","journal-title":"Clin. Cancer Res."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"438","DOI":"10.1038\/cmi.2017.148","article-title":"The Structure, Expression, and Multifaceted Role of Immune-Checkpoint Protein VISTA as a Critical Regulator of Anti-Tumor Immunity, Autoimmunity, and Inflammation","volume":"15","author":"Xu","year":"2018","journal-title":"Cell. Mol. Immunol."},{"key":"ref_65","first-page":"418","article-title":"Beyond CTLA-4 and PD-1, the Generation Z of Negative Checkpoint Regulators","volume":"6","author":"Lines","year":"2015","journal-title":"Front. Immunol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"9693","DOI":"10.1128\/JVI.00888-15","article-title":"Selective Involvement of the Checkpoint Regulator VISTA in Suppression of B-Cell, but Not T-Cell, Responsiveness by Monocytic Myeloid-Derived Suppressor Cells from Mice Infected with an Immunodeficiency-Causing Retrovirus","volume":"89","author":"Green","year":"2015","journal-title":"J. Virol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"4586","DOI":"10.3748\/wjg.v20.i16.4586","article-title":"Inflammation-Related Factors Predicting Prognosis of Gastric Cancer","volume":"20","author":"Chang","year":"2014","journal-title":"World J. Gastroenterol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"1414","DOI":"10.1038\/s41388-019-1078-x","article-title":"The Reciprocal Interaction between Tumor Cells and Activated Fibroblasts Mediated by TNF-\u03b1\/IL-33\/ST2L Signaling Promotes Gastric Cancer Metastasis","volume":"39","author":"Zhou","year":"2020","journal-title":"Oncogene"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1016\/j.imlet.2017.02.006","article-title":"Inflammatory Cytokines IL-17 and TNF-\u03b1 up-Regulate PD-L1 Expression in Human Prostate and Colon Cancer Cells","volume":"184","author":"Wang","year":"2017","journal-title":"Immunol. Lett."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"2387192","DOI":"10.1155\/2022\/2387192","article-title":"CCL3 Promotes Proliferation of Colorectal Cancer Related with TRAF6\/NF-\u039aB Molecular Pathway","volume":"2022","author":"Ma","year":"2022","journal-title":"Contrast Media Mol. Imaging"},{"key":"ref_71","doi-asserted-by":"crossref","unstructured":"Birbrair, A. (2020). Tumor Microenvironment, Springer International Publishing. Advances in Experimental Medicine and Biology.","DOI":"10.1007\/978-3-030-35727-6"},{"key":"ref_72","doi-asserted-by":"crossref","unstructured":"Aldinucci, D., Borghese, C., and Casagrande, N. (2020). The CCL5\/CCR5 Axis in Cancer Progression. Cancers, 12.","DOI":"10.3390\/cancers12071765"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"646252","DOI":"10.3389\/fcell.2021.646252","article-title":"CXCL11 Correlates with Antitumor Immunity and an Improved Prognosis in Colon Cancer","volume":"9","author":"Cao","year":"2021","journal-title":"Front. Cell Dev. Biol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1007\/s00432-020-03463-9","article-title":"Prognostic Significance and Therapeutic Potential of the Immune Checkpoint VISTA in Pancreatic Cancer","volume":"147","author":"Hou","year":"2021","journal-title":"J. Cancer Res. Clin. Oncol."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1097\/CJI.0000000000000343","article-title":"High VISTA Expression Correlates with a Favorable Prognosis in Patients with Colorectal Cancer","volume":"44","author":"Zong","year":"2021","journal-title":"J. Immunother."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"17426","DOI":"10.1038\/s41598-021-96417-1","article-title":"Superpixel Image Segmentation of VISTA Expression in Colorectal Cancer and Its Relationship to the Tumoral Microenvironment","volume":"11","author":"Wu","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"1565","DOI":"10.1126\/science.1203486","article-title":"Cancer Immunoediting: Integrating Immunity\u2019s Roles in Cancer Suppression and Promotion","volume":"331","author":"Schreiber","year":"2011","journal-title":"Science"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"14846","DOI":"10.1073\/pnas.1407447111","article-title":"Disruption of the Immune-Checkpoint VISTA Gene Imparts a Proinflammatory Phenotype with Predisposition to the Development of Autoimmunity","volume":"111","author":"Wang","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"e003382","DOI":"10.1136\/jitc-2021-003382","article-title":"Rationally Targeted Anti-VISTA Antibody That Blockades the C-C\u2019 Loop Region Can Reverse VISTA Immune Suppression and Remodel the Immune Microenvironment to Potently Inhibit Tumor Growth in an Fc Independent Manner","volume":"10","author":"Thakkar","year":"2022","journal-title":"J. Immunother. Cancer"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1016\/j.oraloncology.2016.04.005","article-title":"Differential Contribution of Three Immune Checkpoint (VISTA, CTLA-4, PD-1) Pathways to Antitumor Responses against Squamous Cell Carcinoma","volume":"57","author":"Kondo","year":"2016","journal-title":"Oral. Oncol."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1186\/s12943-018-0928-4","article-title":"Role of the Tumor Microenvironment in PD-L1\/PD-1-Mediated Tumor Immune Escape","volume":"18","author":"Jiang","year":"2019","journal-title":"Mol. Cancer"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1038\/nm.4308","article-title":"VISTA Is an Inhibitory Immune Checkpoint That Is Increased after Ipilimumab Therapy in Patients with Prostate Cancer","volume":"23","author":"Gao","year":"2017","journal-title":"Nat. Med."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1016\/j.it.2020.12.008","article-title":"VISTA: A Mediator of Quiescence and a Promising Target in Cancer Immunotherapy","volume":"42","author":"Yuan","year":"2021","journal-title":"Trends Immunol."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"121083","DOI":"10.1016\/j.lfs.2022.121083","article-title":"VISTA Immune Regulatory Effects in Bypassing Cancer Immunotherapy: Updated","volume":"310","author":"Mortezaee","year":"2022","journal-title":"Life Sci."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"595950","DOI":"10.3389\/fimmu.2020.595950","article-title":"VISTA: A Target to Manage the Innate Cytokine Storm","volume":"11","author":"ElTanbouly","year":"2021","journal-title":"Front. Immunol."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1111\/j.1600-065X.2009.00797.x","article-title":"PSGL-1 Function in Immunity and Steady State Homeostasis","volume":"230","author":"Carlow","year":"2009","journal-title":"Immunol. Rev."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"1190","DOI":"10.1016\/j.immuni.2016.04.015","article-title":"PSGL-1 Is an Immune Checkpoint Regulator That Promotes T Cell Exhaustion","volume":"44","author":"Tinoco","year":"2016","journal-title":"Immunity"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1159\/000217977","article-title":"Implications of Acidic Tumor Microenvironment for Neoplastic Growth and Cancer Treatment: A Computer Analysis","volume":"17","author":"Kraus","year":"1996","journal-title":"Tumor Biol."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1016\/j.semcancer.2017.03.001","article-title":"Cancer Acidity: An Ultimate Frontier of Tumor Immune Escape and a Novel Target of Immunomodulation","volume":"43","author":"Huber","year":"2017","journal-title":"Semin. Cancer Biol."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"100787","DOI":"10.1016\/j.drup.2021.100787","article-title":"Hypoxia as a Driver of Resistance to Immunotherapy","volume":"59","author":"Kopecka","year":"2021","journal-title":"Drug Resist. Updates"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"1079","DOI":"10.1158\/2326-6066.CIR-18-0507","article-title":"Hypoxia-Induced VISTA Promotes the Suppressive Function of Myeloid-Derived Suppressor Cells in the Tumor Microenvironment","volume":"7","author":"Deng","year":"2019","journal-title":"Cancer Immunol. Res."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1186\/1475-2867-13-89","article-title":"Acidic Extracellular Microenvironment and Cancer","volume":"13","author":"Kato","year":"2013","journal-title":"Cancer Cell Int."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"1345","DOI":"10.2174\/138161212799504830","article-title":"Physiology, Pharmacology and Pathophysiology of the PH Regulatory Transport Proteins NHE1 and NBCn1: Similarities, Differences, and Implications for Cancer Therapy","volume":"18","author":"Boedtkjer","year":"2012","journal-title":"Curr. Pharm. Des."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1038\/nrm2820","article-title":"Sensors and Regulators of Intracellular PH","volume":"11","author":"Casey","year":"2010","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"803","DOI":"10.1152\/physrev.00023.2012","article-title":"The Divergence, Actions, Roles, and Relatives of Sodium-Coupled Bicarbonate Transporters","volume":"93","author":"Parker","year":"2013","journal-title":"Physiol. Rev."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1007\/s11515-014-1289-z","article-title":"Amiloride and Guggulsterone Suppression of Esophageal Cancer Cell Growth in Vitro and in Nude Mouse Xenografts","volume":"9","author":"Guan","year":"2014","journal-title":"Front. Biol."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"4113","DOI":"10.1038\/s41467-020-17756-7","article-title":"T-Cells Produce Acidic Niches in Lymph Nodes to Suppress Their Own Effector Functions","volume":"11","author":"Wu","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"2575","DOI":"10.3748\/wjg.v23.i14.2575","article-title":"Effects of Omeprazole in Improving Concurrent Chemoradiotherapy Efficacy in Rectal Cancer","volume":"23","author":"Zhang","year":"2017","journal-title":"World J. Gastroenterol."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"S67","DOI":"10.1038\/d41586-017-08702-7","article-title":"The Benefits of Immunotherapy Combinations","volume":"552","author":"Schmidt","year":"2017","journal-title":"Nature"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"viii41","DOI":"10.1093\/annonc\/mds262","article-title":"Combination Immunotherapy Approaches","volume":"23","author":"Drake","year":"2012","journal-title":"Ann. Oncol."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"705999","DOI":"10.3389\/fimmu.2021.705999","article-title":"Targeted Immunotherapies in Gastrointestinal Cancer: From Molecular Mechanisms to Implications","volume":"12","author":"Wang","year":"2021","journal-title":"Front. Immunol."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1002\/ags3.12180","article-title":"Current Status of Immunotherapy against Gastrointestinal Cancers and Its Biomarkers: Perspective for Precision Immunotherapy","volume":"2","author":"Hazama","year":"2018","journal-title":"Ann. Gastroenterol. Surg."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"eaal4922","DOI":"10.1126\/scitranslmed.aal4922","article-title":"Combined Immune Checkpoint Blockade as a Therapeutic Strategy for BRCA1 -Mutated Breast Cancer","volume":"9","author":"Nolan","year":"2017","journal-title":"Sci. Transl. Med."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1016\/S1470-2045(16)30624-6","article-title":"Nivolumab plus Ipilimumab as First-Line Treatment for Advanced Non-Small-Cell Lung Cancer (CheckMate 012): Results of an Open-Label, Phase 1, Multicohort Study","volume":"18","author":"Hellmann","year":"2017","journal-title":"Lancet Oncol."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"2187","DOI":"10.1084\/jem.20100643","article-title":"Targeting Tim-3 and PD-1 Pathways to Reverse T Cell Exhaustion and Restore Anti-Tumor Immunity","volume":"207","author":"Sakuishi","year":"2010","journal-title":"J. Exp. Med."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"690499","DOI":"10.3389\/fimmu.2021.690499","article-title":"Cell Therapy with TILs: Training and Taming T Cells to Fight Cancer","volume":"12","author":"Kumar","year":"2021","journal-title":"Front. Immunol."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"11774","DOI":"10.1073\/pnas.1410626111","article-title":"Eradication of Metastatic Mouse Cancers Resistant to Immune Checkpoint Blockade by Suppression of Myeloid-Derived Cells","volume":"111","author":"Kim","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"e14569","DOI":"10.1200\/JCO.2021.39.15_suppl.e14569","article-title":"HMBD-002 Is a Novel, Neutralizing, Anti-VISTA Antibody Exhibiting Strong Preclinical Efficacy and Safety, Being Developed as a Monotherapy and in Combination with Pembrolizumab","volume":"39","author":"DiMascio","year":"2021","journal-title":"J. Clin. Oncol."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"A349","DOI":"10.1136\/jitc-2021-SITC2021.324","article-title":"324 Preclinical Evaluation of Anti-VISTA Antibody CI-8993 in a Syngeneic HuVISTA-KI Model","volume":"9","author":"Scott","year":"2021","journal-title":"J. Immunother. Cancer"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"1830524","DOI":"10.1080\/2162402X.2020.1830524","article-title":"Converging Focal Radiation and Immunotherapy in a Preclinical Model of Triple Negative Breast Cancer: Contribution of VISTA Blockade","volume":"9","author":"Pilones","year":"2020","journal-title":"Oncoimmunology"},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"1005","DOI":"10.1080\/13543784.2020.1793956","article-title":"New Immunotherapeutic Drugs in Advanced Non-Small Cell Lung Cancer (NSCLC): From Preclinical to Phase I Clinical Trials","volume":"29","author":"Rocco","year":"2020","journal-title":"Expert. Opin. Investig. Drugs"},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"1066","DOI":"10.1016\/j.semcancer.2021.08.008","article-title":"Immune Functions as a Ligand or a Receptor, Cancer Prognosis Potential, Clinical Implication of VISTA in Cancer Immunotherapy","volume":"86","author":"Im","year":"2021","journal-title":"Semin. Cancer Biol."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"676181","DOI":"10.3389\/fimmu.2021.676181","article-title":"The Role of V-Domain Ig Suppressor of T Cell Activation (VISTA) in Cancer Therapy: Lessons Learned and the Road Ahead","volume":"12","author":"Hosseinkhani","year":"2021","journal-title":"Front. Immunol."},{"key":"ref_114","first-page":"114","article-title":"Phase 1 Study of CA-170, a First-in-Class, Orally Available, Small Molecule Immune Checkpoint Inhibitor (ICI) Dually Targeting VISTA and PD-L1, in Patients with Advanced Solid Tumors or Lymphomas","volume":"6","year":"2018","journal-title":"J. Immunother. Cancer"},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"699","DOI":"10.1038\/s42003-021-02191-1","article-title":"PD-1 Derived CA-170 Is an Oral Immune Checkpoint Inhibitor That Exhibits Preclinical Anti-Tumor Efficacy","volume":"4","author":"Sasikumar","year":"2021","journal-title":"Commun. Biol."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"TPS3099","DOI":"10.1200\/JCO.2017.35.15_suppl.TPS3099","article-title":"Phase 1 Trial of CA-170, a Novel Oral Small Molecule Dual Inhibitor of Immune Checkpoints PD-1 and VISTA, in Patients (Pts) with Advanced Solid Tumor or Lymphomas","volume":"35","author":"Lee","year":"2017","journal-title":"J. Clin. Oncol."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"e000683","DOI":"10.1136\/esmoopen-2020-000683","article-title":"New Emerging Targets in Cancer Immunotherapy: The Role of VISTA","volume":"4","author":"Tagliamento","year":"2019","journal-title":"ESMO Open"},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"185","DOI":"10.2147\/ITT.S260429","article-title":"VISTA: A Promising Target for Cancer Immunotherapy?","volume":"10","author":"Tagliamento","year":"2021","journal-title":"ImmunoTargets Ther."},{"key":"ref_119","doi-asserted-by":"crossref","unstructured":"(2018). 33rd Annual Meeting & Pre-Conference Programs of the Society for Immunotherapy of Cancer (SITC 2018): Late-Breaking Abstracts. J. Immunother. Cancer, 6, 115.","DOI":"10.1186\/s40425-018-0422-y"},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"2368","DOI":"10.1111\/j.1349-7006.2010.01675.x","article-title":"GI24 Enhances Tumor Invasiveness by Regulating Cell Surface Membrane-Type 1 Matrix Metalloproteinase","volume":"101","author":"Sakr","year":"2010","journal-title":"Cancer Sci."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1186\/s40425-016-0190-5","article-title":"A New VISTA on Combination Therapy for Negative Checkpoint Regulator Blockade","volume":"4","author":"Deng","year":"2016","journal-title":"J. Immunother. Cancer"},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"E1239","DOI":"10.1073\/pnas.1718197115","article-title":"Chemotherapy Induces Enrichment of CD47 + \/CD73 + \/PDL1 + Immune Evasive Triple-Negative Breast Cancer Cells","volume":"115","author":"Samanta","year":"2018","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"610","DOI":"10.1158\/2326-6066.CIR-14-0138","article-title":"PD-1 Restrains Radiotherapy-Induced Abscopal Effect","volume":"3","author":"Park","year":"2015","journal-title":"Cancer Immunol. Res."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1016\/j.jtho.2016.10.003","article-title":"The Potential of Combined Immunotherapy and Antiangiogenesis for the Synergistic Treatment of Advanced NSCLC","volume":"12","author":"Manegold","year":"2017","journal-title":"J. Thorac. Oncol."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"500","DOI":"10.1111\/cei.12069","article-title":"Simultaneous Blockade of Programmed Death 1 and Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) Induces Synergistic Anti-Tumour Effect in Vivo","volume":"172","author":"Yasuda","year":"2013","journal-title":"Clin. Exp. Immunol."},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"eaay0524","DOI":"10.1126\/science.aay0524","article-title":"VISTA Is a Checkpoint Regulator for Na\u00efve T Cell Quiescence and Peripheral Tolerance","volume":"367","author":"ElTanbouly","year":"2020","journal-title":"Science"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/12\/9945\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T19:51:30Z","timestamp":1760125890000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/12\/9945"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,6,9]]},"references-count":126,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2023,6]]}},"alternative-id":["ijms24129945"],"URL":"https:\/\/doi.org\/10.3390\/ijms24129945","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,6,9]]}}}