{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,30]],"date-time":"2026-04-30T23:32:23Z","timestamp":1777591943417,"version":"3.51.4"},"reference-count":67,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,7,3]],"date-time":"2025-07-03T00:00:00Z","timestamp":1751500800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,7,3]],"date-time":"2025-07-03T00:00:00Z","timestamp":1751500800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100012533","name":"Minia University","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100012533","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title>\n          <jats:p>Immune checkpoints expressed by immune cells are critical mediators of immune suppression in cancer. Recently, the role of VISTA, an immune checkpoint, in suppressing T cells has been highlighted in several studies. However, its involvement in B-cell acute lymphoblastic leukemia (B-ALL) remains underexplored. In this study, we analyzed the expression of VISTA, the immune-regulatory marker CD244, and its corresponding ligand CD48. Additionally, we examined the expression of the transcription factors FOXD3 and PVRL2 in pediatric patients with B-ALL. Peripheral blood samples from pediatric patients with na\u00efve B-ALL were analyzed using flow cytometry. Additionally, real-time PCR was used to evaluate the downstream regulatory gene FOXD3 expression and the immune regulator PVRL2. VISTA was overexpressed on blasts in B-ALL patients. Also, the frequency of CD3<jats:sup>+<\/jats:sup>CD8<jats:sup>+<\/jats:sup>VISTA<jats:sup>+<\/jats:sup> T cytotoxic cells was significantly higher in patients compared to controls, while CD3<jats:sup>+<\/jats:sup>CD4<jats:sup>+<\/jats:sup>VISTA<jats:sup>+<\/jats:sup> T helper cells were reduced. CD19<jats:sup>+<\/jats:sup>VISTA<jats:sup>+<\/jats:sup> cells were more abundant in the complete remission group compared to the non-complete remission group. FOXD3, a key regulator of VISTA, was significantly downregulated in B-ALL, consistent with VISTA overexpression. The CD244\/CD48 interaction, which can promote anti-tumoral immune responses, showed a reduction in CD3<jats:sup>+<\/jats:sup>CD4<jats:sup>+<\/jats:sup>CD48<jats:sup>+<\/jats:sup> and CD19<jats:sup>+<\/jats:sup>CD48<jats:sup>+<\/jats:sup> cells, while CD3<jats:sup>+<\/jats:sup>CD8<jats:sup>+<\/jats:sup>CD48<jats:sup>+<\/jats:sup> cells were increased. VISTA overexpression and FOXD3 downregulation in B-ALL, alongside altered CD48, and PVRL2 expression, highlight mechanisms of immune evasion. These findings position VISTA as a promising biomarker and target for B-ALL immunotherapy.<\/jats:p>","DOI":"10.1038\/s41598-025-08164-2","type":"journal-article","created":{"date-parts":[[2025,7,3]],"date-time":"2025-07-03T18:04:51Z","timestamp":1751565891000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["VISTA is a potential target for immunotherapy in B-cell acute lymphoblastic leukemia in children"],"prefix":"10.1038","volume":"15","author":[{"given":"Nourhan K","family":"Mohamed","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mohamed A","family":"El-Mokhtar","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Asmaa M","family":"Zahran","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gamal Fadl Mahmoud","family":"Gad","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Reham Ali","family":"Ibrahem","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2025,7,3]]},"reference":[{"key":"8164_CR1","doi-asserted-by":"publisher","first-page":"1146","DOI":"10.1016\/S0140-6736(19)33018-1","volume":"395","author":"F Malard","year":"2020","unstructured":"Malard, F. & Mohty, M. Acute lymphoblastic leukaemia. Lancet 395, 1146\u20131162. https:\/\/doi.org\/10.1016\/S0140-6736(19)33018-1 (2020).","journal-title":"Lancet"},{"key":"8164_CR2","doi-asserted-by":"publisher","first-page":"1408","DOI":"10.1182\/blood-2008-06-164863","volume":"113","author":"D Pulte","year":"2009","unstructured":"Pulte, D., Gondos, A. & Brenner, H. Improvement in survival in younger patients with acute lymphoblastic leukemia from the 1980s to the early 21st century. Blood 113, 1408\u20131411. https:\/\/doi.org\/10.1182\/blood-2008-06-164863 (2009).","journal-title":"Blood"},{"key":"8164_CR3","doi-asserted-by":"publisher","first-page":"902","DOI":"10.1182\/blood-2010-01-262691","volume":"117","author":"S Pillozzi","year":"2011","unstructured":"Pillozzi, S. et al. Chemotherapy resistance in acute lymphoblastic leukemia requires hERG1 channels and is overcome by hERG1 blockers. Blood 117, 902\u2013914. https:\/\/doi.org\/10.1182\/blood-2010-01-262691 (2011).","journal-title":"Blood"},{"key":"8164_CR4","doi-asserted-by":"publisher","unstructured":"Tuong, P. N., Hao, K. & Kim Hoa, N. T. T. Relapsed Childhood Acute Lymphoblastic Leukemia: A Single-Institution Experience. Cureus 12, e9238, (2020). https:\/\/doi.org\/10.7759\/cureus.9238","DOI":"10.7759\/cureus.9238"},{"key":"8164_CR5","doi-asserted-by":"publisher","first-page":"e0265450","DOI":"10.1371\/journal.pone.0265450","volume":"17","author":"E Vazquez-Cornejo","year":"2022","unstructured":"Vazquez-Cornejo, E., Morales-Rios, O., Hernandez-Pliego, G., Cicero-Oneto, C. & Garduno-Espinosa, J. Incidence, severity, and preventability of adverse events during the induction of patients with acute lymphoblastic leukemia in a tertiary care pediatric hospital in Mexico. PLoS One. 17, e0265450. https:\/\/doi.org\/10.1371\/journal.pone.0265450 (2022).","journal-title":"PLoS One"},{"key":"8164_CR6","doi-asserted-by":"publisher","unstructured":"Oskarsson, T. et al. Treatment-related mortality in relapsed childhood acute lymphoblastic leukemia. Pediatr. Blood Cancer. 65 https:\/\/doi.org\/10.1002\/pbc.26909 (2018).","DOI":"10.1002\/pbc.26909"},{"key":"8164_CR7","doi-asserted-by":"publisher","first-page":"227","DOI":"10.1038\/nri3405","volume":"13","author":"L Chen","year":"2013","unstructured":"Chen, L. & Flies, D. B. Molecular mechanisms of T cell co-stimulation and co-inhibition. Nat. Rev. Immunol. 13, 227\u2013242. https:\/\/doi.org\/10.1038\/nri3405 (2013).","journal-title":"Nat. Rev. Immunol."},{"key":"8164_CR8","doi-asserted-by":"publisher","first-page":"660","DOI":"10.1038\/s41422-020-0343-4","volume":"30","author":"X He","year":"2020","unstructured":"He, X. & Xu, C. Immune checkpoint signaling and cancer immunotherapy. Cell. Res. 30, 660\u2013669. https:\/\/doi.org\/10.1038\/s41422-020-0343-4 (2020).","journal-title":"Cell. Res."},{"key":"8164_CR9","doi-asserted-by":"publisher","first-page":"1924","DOI":"10.1158\/0008-5472.CAN-13-1504","volume":"74","author":"JL Lines","year":"2014","unstructured":"Lines, J. L. et al. VISTA is an immune checkpoint molecule for human T cells. Cancer Res. 74, 1924\u20131932. https:\/\/doi.org\/10.1158\/0008-5472.CAN-13-1504 (2014).","journal-title":"Cancer Res."},{"key":"8164_CR10","doi-asserted-by":"publisher","first-page":"1537","DOI":"10.4049\/jimmunol.1100660","volume":"187","author":"DB Flies","year":"2011","unstructured":"Flies, D. B., Wang, S., Xu, H. & Chen, L. Cutting edge: A monoclonal antibody specific for the programmed death-1 homolog prevents graft-versus-host disease in mouse models. J. Immunol. 187, 1537\u20131541. https:\/\/doi.org\/10.4049\/jimmunol.1100660 (2011).","journal-title":"J. Immunol."},{"key":"8164_CR11","doi-asserted-by":"publisher","first-page":"577","DOI":"10.1084\/jem.20100619","volume":"208","author":"L Wang","year":"2011","unstructured":"Wang, L. et al. VISTA, a novel mouse Ig superfamily ligand that negatively regulates T cell responses. J. Exp. Med. 208, 577\u2013592. https:\/\/doi.org\/10.1084\/jem.20100619 (2011).","journal-title":"J. Exp. Med."},{"key":"8164_CR12","doi-asserted-by":"publisher","first-page":"115","DOI":"10.1038\/s41416-018-0313-5","volume":"120","author":"K Mulati","year":"2019","unstructured":"Mulati, K. et al. VISTA expressed in tumour cells regulates T cell function. Br. J. Cancer. 120, 115\u2013127. https:\/\/doi.org\/10.1038\/s41416-018-0313-5 (2019).","journal-title":"Br. J. Cancer"},{"key":"8164_CR13","doi-asserted-by":"publisher","first-page":"1692","DOI":"10.1073\/pnas.1811067116","volume":"116","author":"J Blando","year":"2019","unstructured":"Blando, J. et al. Comparison of immune infiltrates in melanoma and pancreatic cancer highlights VISTA as a potential target in pancreatic cancer. Proc. Natl. Acad. Sci. U S A. 116, 1692\u20131697. https:\/\/doi.org\/10.1073\/pnas.1811067116 (2019).","journal-title":"Proc. Natl. Acad. Sci. U S A"},{"key":"8164_CR14","doi-asserted-by":"publisher","first-page":"1562","DOI":"10.1158\/1078-0432.CCR-17-2542","volume":"24","author":"F Villarroel-Espindola","year":"2018","unstructured":"Villarroel-Espindola, F. et al. Spatially resolved and quantitative analysis of VISTA\/PD-1H as a novel immunotherapy target in human Non-Small cell lung Cancer. Clin. Cancer Res. 24, 1562\u20131573. https:\/\/doi.org\/10.1158\/1078-0432.CCR-17-2542 (2018).","journal-title":"Clin. Cancer Res."},{"key":"8164_CR15","doi-asserted-by":"publisher","unstructured":"Pagliuca, S. et al. Comprehensive transcriptomic analysis of VISTA in acute myeloid leukemia: insights into its prognostic value. Int. J. Mol. Sci. 23 https:\/\/doi.org\/10.3390\/ijms232314885 (2022).","DOI":"10.3390\/ijms232314885"},{"key":"8164_CR16","doi-asserted-by":"publisher","first-page":"748","DOI":"10.19746\/j.cnki.issn.1009-2137.2020.03.006","volume":"28","author":"MJ Ge","year":"2020","unstructured":"Ge, M. J. et al. [Expression and significance of PD-1, TIM-3 and VISTA on T cell of acute myeloid leukemia patients]. Zhongguo Shi Yan Xue Ye Xue Za Zhi. 28, 748\u2013752. https:\/\/doi.org\/10.19746\/j.cnki.issn.1009-2137.2020.03.006 (2020).","journal-title":"Zhongguo Shi Yan Xue Ye Xue Za Zhi"},{"key":"8164_CR17","doi-asserted-by":"publisher","unstructured":"Mo, J. et al. Targeting STAT3-VISTA axis to suppress tumor aggression and burden in acute myeloid leukemia. J. Hematol. Oncol. 16 https:\/\/doi.org\/10.1186\/s13045-023-01410-y (2023).","DOI":"10.1186\/s13045-023-01410-y"},{"key":"8164_CR18","doi-asserted-by":"publisher","first-page":"1086102","DOI":"10.3389\/fimmu.2023.1086102","volume":"14","author":"AS Martin","year":"2023","unstructured":"Martin, A. S. et al. VISTA expression and patient selection for immune-based anticancer therapy. Front. Immunol. 14, 1086102. https:\/\/doi.org\/10.3389\/fimmu.2023.1086102 (2023).","journal-title":"Front. Immunol."},{"key":"8164_CR19","doi-asserted-by":"publisher","first-page":"1311658","DOI":"10.3389\/fimmu.2023.1311658","volume":"14","author":"S Iadonato","year":"2023","unstructured":"Iadonato, S. et al. A highly potent anti-VISTA antibody KVA12123 - a new immune checkpoint inhibitor and a promising therapy against poorly Immunogenic tumors. Front. Immunol. 14, 1311658. https:\/\/doi.org\/10.3389\/fimmu.2023.1311658 (2023).","journal-title":"Front. Immunol."},{"key":"8164_CR20","unstructured":"Clinicaltrials.gov."},{"key":"8164_CR21","doi-asserted-by":"publisher","first-page":"1286","DOI":"10.15252\/embr.201438643","volume":"15","author":"L Zhu","year":"2014","unstructured":"Zhu, L., Zhang, S. & Jin, Y. Foxd3 suppresses NFAT-mediated differentiation to maintain self-renewal of embryonic stem cells. EMBO Rep. 15, 1286\u20131296. https:\/\/doi.org\/10.15252\/embr.201438643 (2014).","journal-title":"EMBO Rep."},{"key":"8164_CR22","doi-asserted-by":"publisher","unstructured":"Rosenbaum, S. R. et al. FOXD3 Regulates VISTA Expression in Melanoma. Cell Rep 30, 510\u2013524 e516, (2020). https:\/\/doi.org\/10.1016\/j.celrep.2019.12.036","DOI":"10.1016\/j.celrep.2019.12.036"},{"key":"8164_CR23","first-page":"23","volume":"7","author":"F Namazi","year":"2020","unstructured":"Namazi, F., Ketabchi, F., Moghimi, M., Nasrin, H. & Raisinia, M. M. Expression of miR-485-3p and its target FOXD3 in chronic lymphocytic leukemia. Int. J. Med. Lab. 7, 23\u201329 (2020).","journal-title":"Int. J. Med. Lab."},{"key":"8164_CR24","doi-asserted-by":"publisher","first-page":"788","DOI":"10.1080\/10428190902803677","volume":"50","author":"M Jak","year":"2009","unstructured":"Jak, M. et al. Enhanced formation and survival of CD4\u2009+\u2009CD25hi Foxp3\u2009+\u2009T-cells in chronic lymphocytic leukemia. Leuk. Lymphoma. 50, 788\u2013801. https:\/\/doi.org\/10.1080\/10428190902803677 (2009).","journal-title":"Leuk. Lymphoma"},{"key":"8164_CR25","doi-asserted-by":"publisher","first-page":"e0127976","DOI":"10.1371\/journal.pone.0127976","volume":"10","author":"W Du","year":"2015","unstructured":"Du, W. et al. Decreased FOXD3 expression is associated with poor prognosis in patients with High-Grade gliomas. PLoS One. 10, e0127976. https:\/\/doi.org\/10.1371\/journal.pone.0127976 (2015).","journal-title":"PLoS One"},{"key":"8164_CR26","doi-asserted-by":"publisher","first-page":"13433","DOI":"10.1073\/pnas.0906455106","volume":"106","author":"SS Chen","year":"2009","unstructured":"Chen, S. S. et al. Epigenetic changes during disease progression in a murine model of human chronic lymphocytic leukemia. Proc. Natl. Acad. Sci. U S A. 106, 13433\u201313438. https:\/\/doi.org\/10.1073\/pnas.0906455106 (2009).","journal-title":"Proc. Natl. Acad. Sci. U S A"},{"key":"8164_CR27","doi-asserted-by":"publisher","first-page":"5048","DOI":"10.18632\/oncotarget.13790","volume":"8","author":"K Li","year":"2017","unstructured":"Li, K. et al. FOXD3 is a tumor suppressor of colon cancer by inhibiting EGFR-Ras-Raf-MEK-ERK signal pathway. Oncotarget 8, 5048\u20135056. https:\/\/doi.org\/10.18632\/oncotarget.13790 (2017).","journal-title":"Oncotarget"},{"key":"8164_CR28","doi-asserted-by":"publisher","first-page":"234","DOI":"10.1034\/j.1600-065x.2001.1810120.x","volume":"181","author":"KS Boles","year":"2001","unstructured":"Boles, K. S., Stepp, S. E., Bennett, M., Kumar, V. & Mathew, P. A. 2B4 (CD244) and CS1: novel members of the CD2 subset of the Immunoglobulin superfamily molecules expressed on natural killer cells and other leukocytes. Immunol. Rev. 181, 234\u2013249. https:\/\/doi.org\/10.1034\/j.1600-065x.2001.1810120.x (2001).","journal-title":"Immunol. Rev."},{"key":"8164_CR29","doi-asserted-by":"publisher","first-page":"489","DOI":"10.1016\/j.molimm.2004.07.032","volume":"42","author":"ME McNerney","year":"2005","unstructured":"McNerney, M. E., Lee, K. M. & Kumar, V. 2B4 (CD244) is a non-MHC binding receptor with multiple functions on natural killer cells and CD8\u2009+\u2009T cells. Mol. Immunol. 42, 489\u2013494. https:\/\/doi.org\/10.1016\/j.molimm.2004.07.032 (2005).","journal-title":"Mol. Immunol."},{"key":"8164_CR30","doi-asserted-by":"publisher","first-page":"1612","DOI":"10.1182\/blood-2012-09-457531","volume":"121","author":"JC Riches","year":"2013","unstructured":"Riches, J. C. et al. T cells from CLL patients exhibit features of T-cell exhaustion but retain capacity for cytokine production. Blood 121, 1612\u20131621. https:\/\/doi.org\/10.1182\/blood-2012-09-457531 (2013).","journal-title":"Blood"},{"key":"8164_CR31","doi-asserted-by":"publisher","first-page":"4646","DOI":"10.4049\/jimmunol.176.8.4646","volume":"176","author":"B Messmer","year":"2006","unstructured":"Messmer, B., Eissmann, P., Stark, S. & Watzl, C. CD48 stimulation by 2B4 (CD244)-expressing targets activates human NK cells. J. Immunol. 176, 4646\u20134650. https:\/\/doi.org\/10.4049\/jimmunol.176.8.4646 (2006).","journal-title":"J. Immunol."},{"key":"8164_CR32","first-page":"179","volume":"8","author":"AJ Henniker","year":"1990","unstructured":"Henniker, A. J., Bradstock, K. F., Grimsley, P. & Atkinson, M. K. A novel non-lineage antigen on human leucocytes: Characterization with two CD-48 monoclonal antibodies. Dis. Markers. 8, 179\u2013190 (1990).","journal-title":"Dis. Markers"},{"key":"8164_CR33","doi-asserted-by":"publisher","first-page":"103958","DOI":"10.1016\/j.cellimm.2019.103958","volume":"344","author":"X Zhang","year":"2019","unstructured":"Zhang, X. et al. TIGIT expression is upregulated in T cells and causes T cell dysfunction independent of PD-1 and Tim-3 in adult B lineage acute lymphoblastic leukemia. Cell. Immunol. 344, 103958. https:\/\/doi.org\/10.1016\/j.cellimm.2019.103958 (2019).","journal-title":"Cell. Immunol."},{"key":"8164_CR34","doi-asserted-by":"publisher","first-page":"5269","DOI":"10.1038\/s41388-018-0288-y","volume":"37","author":"H Stamm","year":"2018","unstructured":"Stamm, H. et al. Immune checkpoints PVR and PVRL2 are prognostic markers in AML and their Blockade represents a new therapeutic option. Oncogene 37, 5269\u20135280. https:\/\/doi.org\/10.1038\/s41388-018-0288-y (2018).","journal-title":"Oncogene"},{"key":"8164_CR35","doi-asserted-by":"publisher","first-page":"101042831769504","DOI":"10.1177\/1010428317695040","volume":"39","author":"G Khakpour","year":"2017","unstructured":"Khakpour, G. et al. Methylomics of breast cancer: Seeking epimarkers in peripheral blood of young subjects. Tumour Biol. 39, 1010428317695040. https:\/\/doi.org\/10.1177\/1010428317695040 (2017).","journal-title":"Tumour Biol."},{"key":"8164_CR36","doi-asserted-by":"publisher","first-page":"6","DOI":"10.1186\/s40364-020-0185-8","volume":"8","author":"J Tan","year":"2020","unstructured":"Tan, J. et al. Increased PD-1\u2009+\u2009Tim-3\u2009+\u2009exhausted T cells in bone marrow May influence the clinical outcome of patients with AML. Biomark. Res. 8, 6. https:\/\/doi.org\/10.1186\/s40364-020-0185-8 (2020).","journal-title":"Biomark. Res."},{"key":"8164_CR37","doi-asserted-by":"publisher","first-page":"101308","DOI":"10.1016\/j.smim.2019.101308","volume":"42","author":"MA ElTanbouly","year":"2019","unstructured":"ElTanbouly, M. A., Croteau, W., Noelle, R. J. & Lines, J. L. VISTA: a novel immunotherapy target for normalizing innate and adaptive immunity. Semin Immunol. 42, 101308. https:\/\/doi.org\/10.1016\/j.smim.2019.101308 (2019).","journal-title":"Semin Immunol."},{"key":"8164_CR38","doi-asserted-by":"publisher","first-page":"1933","DOI":"10.1158\/0008-5472.CAN-13-1506","volume":"74","author":"I Le Mercier","year":"2014","unstructured":"Le Mercier, I. et al. VISTA regulates the development of protective antitumor immunity. Cancer Res. 74, 1933\u20131944. https:\/\/doi.org\/10.1158\/0008-5472.CAN-13-1506 (2014).","journal-title":"Cancer Res."},{"key":"8164_CR39","doi-asserted-by":"publisher","first-page":"54","DOI":"10.1016\/j.oraloncology.2016.04.005","volume":"57","author":"Y Kondo","year":"2016","unstructured":"Kondo, Y. et al. Differential contribution of three immune checkpoint (VISTA, CTLA-4, PD-1) pathways to antitumor responses against squamous cell carcinoma. Oral Oncol. 57, 54\u201360. https:\/\/doi.org\/10.1016\/j.oraloncology.2016.04.005 (2016).","journal-title":"Oral Oncol."},{"key":"8164_CR40","doi-asserted-by":"publisher","first-page":"e1469594","DOI":"10.1080\/2162402X.2018.1469594","volume":"7","author":"L Wang","year":"2018","unstructured":"Wang, L. et al. VISTA is highly expressed on MDSCs and mediates an Inhibition of T cell response in patients with AML. Oncoimmunology 7, e1469594. https:\/\/doi.org\/10.1080\/2162402X.2018.1469594 (2018).","journal-title":"Oncoimmunology"},{"key":"8164_CR41","doi-asserted-by":"publisher","unstructured":"Thakkar, D. et al. 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. J. Immunother Cancer. 10 https:\/\/doi.org\/10.1136\/jitc-2021-003382 (2022).","DOI":"10.1136\/jitc-2021-003382"},{"key":"8164_CR42","doi-asserted-by":"publisher","first-page":"14846","DOI":"10.1073\/pnas.1407447111","volume":"111","author":"L Wang","year":"2014","unstructured":"Wang, L. et al. Disruption of the immune-checkpoint VISTA gene imparts a Proinflammatory phenotype with predisposition to the development of autoimmunity. Proc. Natl. Acad. Sci. U S A. 111, 14846\u201314851. https:\/\/doi.org\/10.1073\/pnas.1407447111 (2014).","journal-title":"Proc. Natl. Acad. Sci. U S A"},{"key":"8164_CR43","doi-asserted-by":"publisher","first-page":"1966","DOI":"10.1172\/JCI74589","volume":"124","author":"DB Flies","year":"2014","unstructured":"Flies, D. B. et al. Coinhibitory receptor PD-1H preferentially suppresses CD4(+) T cell-mediated immunity. J. Clin. Invest. 124, 1966\u20131975. https:\/\/doi.org\/10.1172\/JCI74589 (2014).","journal-title":"J. Clin. Invest."},{"key":"8164_CR44","doi-asserted-by":"publisher","unstructured":"ElTanbouly, M. A. et al. VISTA is a checkpoint regulator for Naive T cell quiescence and peripheral tolerance. Science 367 https:\/\/doi.org\/10.1126\/science.aay0524 (2020).","DOI":"10.1126\/science.aay0524"},{"key":"8164_CR45","doi-asserted-by":"publisher","first-page":"523","DOI":"10.1179\/1607845415Y.0000000025","volume":"20","author":"SZ Idris","year":"2015","unstructured":"Idris, S. Z. et al. Increased regulatory T cells in acute lymphoblastic leukemia patients. Hematology 20, 523\u2013529. https:\/\/doi.org\/10.1179\/1607845415Y.0000000025 (2015).","journal-title":"Hematology"},{"key":"8164_CR46","doi-asserted-by":"publisher","first-page":"124","DOI":"10.1111\/imm.12237","volume":"142","author":"K Bhattacharya","year":"2014","unstructured":"Bhattacharya, K., Chandra, S. & Mandal, C. Critical stoichiometric ratio of CD4(+) CD25(+) FoxP3(+) regulatory T cells and CD4(+) CD25(-) responder T cells influence immunosuppression in patients with B-cell acute lymphoblastic leukaemia. Immunology 142, 124\u2013139. https:\/\/doi.org\/10.1111\/imm.12237 (2014).","journal-title":"Immunology"},{"key":"8164_CR47","doi-asserted-by":"publisher","first-page":"28","DOI":"10.1159\/000351429","volume":"131","author":"I Lustfeld","year":"2014","unstructured":"Lustfeld, I. et al. High proportions of CD4(+) T cells among residual bone marrow T cells in childhood acute lymphoblastic leukemia are associated with favorable early responses. Acta Haematol. 131, 28\u201336. https:\/\/doi.org\/10.1159\/000351429 (2014).","journal-title":"Acta Haematol."},{"key":"8164_CR48","doi-asserted-by":"publisher","first-page":"421","DOI":"10.3892\/ol.2011.499","volume":"3","author":"CP Wu","year":"2012","unstructured":"Wu, C. P., Qing, X., Wu, C. Y., Zhu, H. & Zhou, H. Y. Immunophenotype and increased presence of CD4(+)CD25(+) regulatory T cells in patients with acute lymphoblastic leukemia. Oncol. Lett. 3, 421\u2013424. https:\/\/doi.org\/10.3892\/ol.2011.499 (2012).","journal-title":"Oncol. Lett."},{"key":"8164_CR49","doi-asserted-by":"publisher","unstructured":"Ustun, C., Miller, J. S., Munn, D. H., Weisdorf, D. J. & Blazar, B. R. Regulatory T cells in acute myelogenous leukemia: is it time for immunomodulation? Blood 118, 5084\u20135095, (2011). https:\/\/doi.org\/10.1182\/blood-2011-07-365817","DOI":"10.1182\/blood-2011-07-365817"},{"key":"8164_CR50","doi-asserted-by":"publisher","first-page":"562","DOI":"10.3324\/haematol.2016.151100","volume":"102","author":"M Palma","year":"2017","unstructured":"Palma, M. et al. T cells in chronic lymphocytic leukemia display dysregulated expression of immune checkpoints and activation markers. Haematologica 102, 562\u2013572. https:\/\/doi.org\/10.3324\/haematol.2016.151100 (2017).","journal-title":"Haematologica"},{"key":"8164_CR51","doi-asserted-by":"publisher","first-page":"2219554","DOI":"10.1080\/16078454.2023.2219554","volume":"28","author":"J Fang","year":"2023","unstructured":"Fang, J. et al. Aberrant expression of T cell activation markers and upregulation of Tregs in bone marrow and peripheral blood in acute myeloid leukemia patients. Hematology 28, 2219554. https:\/\/doi.org\/10.1080\/16078454.2023.2219554 (2023).","journal-title":"Hematology"},{"key":"8164_CR52","doi-asserted-by":"publisher","first-page":"2642","DOI":"10.1182\/bloodadvances.2019000360","volume":"3","author":"I de Weerdt","year":"2019","unstructured":"de Weerdt, I. et al. Distinct immune composition in lymph node and peripheral blood of CLL patients is reshaped during venetoclax treatment. Blood Adv. 3, 2642\u20132652. https:\/\/doi.org\/10.1182\/bloodadvances.2019000360 (2019).","journal-title":"Blood Adv."},{"key":"8164_CR53","doi-asserted-by":"publisher","first-page":"44","DOI":"10.1186\/s12935-019-0755-8","volume":"19","author":"GF Luo","year":"2019","unstructured":"Luo, G. F. et al. FOXD3 May be a new cellular target biomarker as a hypermethylation gene in human ovarian cancer. Cancer Cell. Int. 19, 44. https:\/\/doi.org\/10.1186\/s12935-019-0755-8 (2019).","journal-title":"Cancer Cell. Int."},{"key":"8164_CR54","doi-asserted-by":"publisher","first-page":"21504","DOI":"10.1038\/s41598-021-00835-0","volume":"11","author":"A Ghouzlani","year":"2021","unstructured":"Ghouzlani, A., Lakhdar, A., Rafii, S., Karkouri, M. & Badou, A. The immune checkpoint VISTA exhibits high expression levels in human gliomas and associates with a poor prognosis. Sci. Rep. 11, 21504. https:\/\/doi.org\/10.1038\/s41598-021-00835-0 (2021).","journal-title":"Sci. Rep."},{"key":"8164_CR55","doi-asserted-by":"publisher","first-page":"8159","DOI":"10.4049\/jimmunol.180.12.8159","volume":"180","author":"LK Chlewicki","year":"2008","unstructured":"Chlewicki, L. K., Velikovsky, C. A., Balakrishnan, V., Mariuzza, R. A. & Kumar, V. Molecular basis of the dual functions of 2B4 (CD244). J. Immunol. 180, 8159\u20138167. https:\/\/doi.org\/10.4049\/jimmunol.180.12.8159 (2008).","journal-title":"J. Immunol."},{"key":"8164_CR56","doi-asserted-by":"publisher","first-page":"463","DOI":"10.21147\/j.issn.1000-9604.2017.05.11","volume":"29","author":"J Tan","year":"2017","unstructured":"Tan, J. et al. Higher PD-1 expression concurrent with exhausted CD8\u2009+\u2009T cells in patients with de Novo acute myeloid leukemia. Chin. J. Cancer Res. 29, 463\u2013470. https:\/\/doi.org\/10.21147\/j.issn.1000-9604.2017.05.11 (2017).","journal-title":"Chin. J. Cancer Res."},{"key":"8164_CR57","doi-asserted-by":"publisher","first-page":"113","DOI":"10.1007\/BF00210824","volume":"33","author":"HA Vaughan","year":"1991","unstructured":"Vaughan, H. A., Henning, M. M., Purcell, D. F., McKenzie, I. F. & Sandrin, M. S. The isolation of cDNA clones for CD48. Immunogenetics 33, 113\u2013117. https:\/\/doi.org\/10.1007\/BF00210824 (1991).","journal-title":"Immunogenetics"},{"key":"8164_CR58","doi-asserted-by":"publisher","first-page":"1339","DOI":"10.1084\/jem.173.6.1339","volume":"173","author":"P Del Porto","year":"1991","unstructured":"Del Porto, P. et al. TCT.1, a target molecule for gamma\/delta T cells, is encoded by an Immunoglobulin superfamily gene (Blast-1) located in the CD1 region of human chromosome 1. J. Exp. Med. 173, 1339\u20131344. https:\/\/doi.org\/10.1084\/jem.173.6.1339 (1991).","journal-title":"J. Exp. Med."},{"key":"8164_CR59","doi-asserted-by":"publisher","first-page":"10","DOI":"10.1016\/j.clim.2016.01.008","volume":"164","author":"SL McArdel","year":"2016","unstructured":"McArdel, S. L., Terhorst, C. & Sharpe, A. H. Roles of CD48 in regulating immunity and tolerance. Clin. Immunol. 164, 10\u201320. https:\/\/doi.org\/10.1016\/j.clim.2016.01.008 (2016).","journal-title":"Clin. Immunol."},{"key":"8164_CR60","doi-asserted-by":"publisher","first-page":"1535","DOI":"10.1182\/blood-2013-09-526590","volume":"123","author":"S Elias","year":"2014","unstructured":"Elias, S. et al. Immune evasion by oncogenic proteins of acute myeloid leukemia. Blood 123, 1535\u20131543. https:\/\/doi.org\/10.1182\/blood-2013-09-526590 (2014).","journal-title":"Blood"},{"key":"8164_CR61","doi-asserted-by":"publisher","first-page":"2547","DOI":"10.1182\/blood.V118.21.2547.2547","volume":"118","author":"L Brent","year":"2011","unstructured":"Brent, L. et al. High-Throughput screening by flow cytometry identifies reduced expression of CD48 as a universal characteristic of T-ALL and a suitable target for minimal residual disease (MRD) detection. Blood 118, 2547 (2011).","journal-title":"Blood"},{"key":"8164_CR62","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1007\/s12272-021-01365-z","volume":"45","author":"EJ Park","year":"2022","unstructured":"Park, E. J. et al. CD48-expressing non-small-cell lung cancer cells are susceptible to natural killer cell-mediated cytotoxicity. Arch. Pharm. Res. 45, 1\u201310. https:\/\/doi.org\/10.1007\/s12272-021-01365-z (2022).","journal-title":"Arch. Pharm. Res."},{"key":"8164_CR63","doi-asserted-by":"publisher","first-page":"e1004000","DOI":"10.1371\/journal.ppat.1004000","volume":"10","author":"A Zarama","year":"2014","unstructured":"Zarama, A. et al. Cytomegalovirus m154 hinders CD48 cell-surface expression and promotes viral escape from host natural killer cell control. PLoS Pathog. 10, e1004000. https:\/\/doi.org\/10.1371\/journal.ppat.1004000 (2014).","journal-title":"PLoS Pathog"},{"key":"8164_CR64","doi-asserted-by":"publisher","first-page":"90","DOI":"10.1006\/cimm.1996.0297","volume":"174","author":"EN Klyushnenkova","year":"1996","unstructured":"Klyushnenkova, E. N., Li, L., Armitage, R. J. & Choi, Y. S. CD48 delivers an accessory signal for CD40-mediated activation of human B cells. Cell. Immunol. 174, 90\u201398. https:\/\/doi.org\/10.1006\/cimm.1996.0297 (1996).","journal-title":"Cell. Immunol."},{"key":"8164_CR65","doi-asserted-by":"publisher","first-page":"178","DOI":"10.1038\/sj.leu.2402363","volume":"16","author":"J Hulkkonen","year":"2002","unstructured":"Hulkkonen, J., Vilpo, L., Hurme, M. & Vilpo, J. Surface antigen expression in chronic lymphocytic leukemia: clustering analysis, interrelationships and effects of chromosomal abnormalities. Leukemia 16, 178\u2013185. https:\/\/doi.org\/10.1038\/sj.leu.2402363 (2002).","journal-title":"Leukemia"},{"key":"8164_CR66","doi-asserted-by":"publisher","first-page":"754","DOI":"10.4049\/jimmunol.166.2.754","volume":"166","author":"VP Patel","year":"2001","unstructured":"Patel, V. P., Moran, M., Low, T. A. & Miceli, M. C. A molecular framework for two-step T cell signaling: Lck Src homology 3 mutations discriminate distinctly regulated lipid raft reorganization events. J. Immunol. 166, 754\u2013764. https:\/\/doi.org\/10.4049\/jimmunol.166.2.754 (2001).","journal-title":"J. Immunol."},{"key":"8164_CR67","doi-asserted-by":"publisher","first-page":"19242","DOI":"10.1074\/jbc.272.31.19242","volume":"272","author":"TM Stulnig","year":"1997","unstructured":"Stulnig, T. M. et al. Signal transduction via Glycosyl phosphatidylinositol-anchored proteins in T cells is inhibited by Lowering cellular cholesterol. J. Biol. Chem. 272, 19242\u201319247. https:\/\/doi.org\/10.1074\/jbc.272.31.19242 (1997).","journal-title":"J. Biol. Chem."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-025-08164-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-025-08164-2","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-025-08164-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,7,3]],"date-time":"2025-07-03T18:04:53Z","timestamp":1751565893000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-025-08164-2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,3]]},"references-count":67,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["8164"],"URL":"https:\/\/doi.org\/10.1038\/s41598-025-08164-2","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,7,3]]},"assertion":[{"value":"28 July 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"19 June 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"3 July 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare no competing interests.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"The experimental protocol was approved by the Minia University Faculty of Pharmacy Ethics Committee under approval number MPEC (230505), and all methods were performed in accordance with the relevant guidelines and regulations.\u201d","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval"}},{"value":"Informed consent was obtained from a parent and\/or legal guardian of all individual participants included in the study.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent to participate"}},{"value":"Not applicable.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent to publish"}}],"article-number":"23809"}}