{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T10:06:25Z","timestamp":1781085985694,"version":"3.54.1"},"reference-count":32,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T00:00:00Z","timestamp":1781049600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"MUSC Department of Neurosurgery"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background\/Objectives: Pediatric group 3 (G3) medulloblastomas (MB) are therapy resistant and have a significantly worse prognosis than the other MB subtypes. Aggressive radiation\/chemotherapy improves survival, but potential long-term comorbidities include neurocognitive deficits. In previous work, we demonstrated that low-dose X-ray radiation (LDXR) acts as an immunological adjuvant. Recent studies have demonstrated that galectin-3 (Gal-3) expression in MB tumors accelerates M2 macrophage infiltration and restricts T cell receptor (TCR)-mediated signaling. Immunotherapy with an agonistic anti-4-1BB monoclonal antibody (mAb) activates CD8+ T cells, promoting their survival and acquisition of potent cytolytic properties. Building on these findings, we hypothesized that immune priming via sublethal LDXR, combined with a Gal-3 inhibitor and an anti-4-1BB mAb, would boost anti-tumor effects, resulting in survival benefits. Methods: We tested this hypothesis in vitro in co-cultures of human MB cells and in vivo, in an immunocompetent G3MB mouse model (MP1). Treatment effects were assessed using Western blot, flow cytometry, hematoxylin and eosin (H&amp;E) staining, immunofluorescence imaging, and analysis of cytokine and chemokine expression. Results: Our data demonstrated higher Gal-3 expression in MB patient-derived tumor tissue than in non-tumor tissue. LDXR modulated major histocompatibility complex molecules, and, combined with a Gal-3 inhibitor and an anti-4-1BB mAb, altered T-cell\/tumor-cell interactions, enhanced T-cell-mediated MB cell death, and shifted cytokine production to drive microglial polarization toward the M1 subtype. Furthermore, H&amp;E-stained tumor sections showed a ~70% reduction in tumor size compared with untreated controls. Conclusions: These preclinical findings suggest that combining immune priming with sublethal LDXR, Gal-3 inhibition, and 4-1BB activation may be an effective treatment strategy for G3MB.<\/jats:p>","DOI":"10.3390\/cancers18121890","type":"journal-article","created":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T09:25:17Z","timestamp":1781083517000},"page":"1890","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Effects of Combining Immune-Priming Sub-Lethal Low-Dose Radiation with 4-1BB Activation and Gal-3 Blockade in In Vitro and Preclinical Group-3 Medulloblastoma Models"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0086-4760","authenticated-orcid":false,"given":"Arabinda","family":"Das","sequence":"first","affiliation":[{"name":"Department of Neurosurgery, Medical University of South Carolina, Charleston, SC 29425, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Connor","family":"Stephenson","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Medical University of South Carolina, Charleston, SC 29425, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel G.","family":"McDonald","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Medical University of South Carolina, Charleston, SC 29425, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julian E.","family":"Bailes","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Endeavor Health, Evanston, IL 60201, USA"},{"name":"Pritzker School of Medicine, University of Chicago, Chicago, IL 60637, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5860-8452","authenticated-orcid":false,"given":"David","family":"Cachia","sequence":"additional","affiliation":[{"name":"Department of Medicine\/Hematology-Oncology, UMass Memorial Health, Worcester, MA 01605, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ramin","family":"Eskandari","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Medical University of South Carolina, Charleston, SC 29425, USA"},{"name":"Department of Pediatric Neurosurgery, Medical University of South Carolina, Charleston, SC 29406, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1061","DOI":"10.1016\/j.tips.2017.09.002","article-title":"Challenges and Recent Advances in Medulloblastoma Therapy","volume":"38","author":"Kumar","year":"2017","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1627","DOI":"10.1200\/JCO.2008.17.9432","article-title":"Outcome Prediction in Pediatric Medulloblastoma Based on DNA Copy-Number Aberrations of Chromosomes 6q and 17q and the MYC and MYCN Loci","volume":"27","author":"Pfister","year":"2009","journal-title":"J. Clin. Oncol."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Menyh\u00e1rt, O., Giangaspero, F., and Gy\u0151rffy, B. (2019). Molecular Markers and Potential Therapeutic Targets in Non-WNT\/Non-SHH (Group 3 and Group 4) Medulloblastomas. J. Hematol. Oncol., 12.","DOI":"10.1186\/s13045-019-0712-y"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1350","DOI":"10.1002\/pbc.24496","article-title":"Intellectual and Academic Outcome Following Two Chemotherapy Regimens and Radiotherapy for Average-risk Medulloblastoma: COG A9961","volume":"60","author":"Ris","year":"2013","journal-title":"Pediatr. Blood Cancer"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1016\/j.redox.2016.08.002","article-title":"The Impact of High and Low Dose Ionising Radiation on the Central Nervous System","volume":"9","author":"Betlazar","year":"2016","journal-title":"Redox Biol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1457","DOI":"10.1158\/1078-0432.CCR-14-1144","article-title":"Tumor-Associated Macrophages in SHH Subgroup of Medulloblastomas","volume":"21","author":"Margol","year":"2015","journal-title":"Clin. Cancer Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"326","DOI":"10.1016\/j.ccell.2017.02.009","article-title":"The Microenvironmental Landscape of Brain Tumors","volume":"31","author":"Quail","year":"2017","journal-title":"Cancer Cell"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"E4041","DOI":"10.1073\/pnas.1720948115","article-title":"Macrophages Impede CD8 T Cells from Reaching Tumor Cells and Limit the Efficacy of Anti\u2013PD-1 Treatment","volume":"115","author":"Peranzoni","year":"2018","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"508","DOI":"10.1016\/j.ccell.2016.03.002","article-title":"Medulloblastoma Genotype Dictates Blood Brain Barrier Phenotype","volume":"29","author":"Phoenix","year":"2016","journal-title":"Cancer Cell"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1038\/s41568-019-0224-7","article-title":"Brain Immunology and Immunotherapy in Brain Tumours","volume":"20","author":"Sampson","year":"2019","journal-title":"Nat. Rev. Cancer"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"e1434467","DOI":"10.1080\/2162402X.2018.1434467","article-title":"The role of Galectin-3 in modulating tumor growth and immunosuppression within the tumor microenvironment","volume":"7","author":"Farhad","year":"2018","journal-title":"Oncoimmunology"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1016\/j.cca.2014.01.019","article-title":"Galectin-3 in Cancer","volume":"431","author":"Song","year":"2014","journal-title":"Clin. Chim. Acta"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"7228","DOI":"10.1158\/0008-5472.CAN-08-1245","article-title":"Tumor-Associated Galectin-3 Modulates the Function of Tumor-Reactive T Cells","volume":"68","author":"Peng","year":"2008","journal-title":"Cancer Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2650","DOI":"10.4049\/jimmunol.180.4.2650","article-title":"Regulation of Alternative Macrophage Activation by Galectin-3","volume":"180","author":"MacKinnon","year":"2008","journal-title":"J. Immunol."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Compagno, D., Tiraboschi, C., Garcia, J.D., Rond\u00f3n, Y., Corapi, E., Velazquez, C., and Laderach, D.J. (2020). Galectins as Checkpoints of the Immune System in Cancers, Their Clinical Relevance, and Implication in Clinical Trials. Biomolecules, 10.","DOI":"10.3390\/biom10050750"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"4897","DOI":"10.4049\/jimmunol.168.10.4897","article-title":"4-1BB Ligand-Mediated Costimulation of Human T Cells Induces CD4 and CD8 T Cell Expansion, Cytokine Production, and the Development of Cytolytic Effector Function","volume":"168","author":"Wen","year":"2002","journal-title":"J. Immunol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1084\/jem.186.1.47","article-title":"4-1BB Costimulatory Signals Preferentially Induce CD8+ T Cell Proliferation and Lead to the Amplification In Vivo of Cytotoxic T Cell Responses","volume":"186","author":"Shuford","year":"1997","journal-title":"J. Exp. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1158\/2326-6066.CIR-16-0364","article-title":"4-1BB-Enhanced Expansion of CD8+ TIL from Triple-Negative Breast Cancer Unveils Mutation-Specific CD8+ T Cells","volume":"5","author":"Harao","year":"2017","journal-title":"Cancer Immunol. Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1111\/cei.12344","article-title":"Low and Moderate Doses of Ionizing Radiation up to 2 Gy Modulate Transmigration and Chemotaxis of Activated Macrophages, Provoke an Anti-Inflammatory Cytokine Milieu, but Do Not Impact upon Viability and Phagocytic Function","volume":"179","author":"Wunderlich","year":"2014","journal-title":"Clin. Exp. Immunol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1007\/s00381-016-3305-x","article-title":"Immunological Low-Dose Radiation Modulates the Pediatric Medulloblastoma Antigens and Enhances Antibody-Dependent Cellular Cytotoxicity","volume":"33","author":"Das","year":"2017","journal-title":"Childs Nerv. Syst."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"589","DOI":"10.1016\/j.ccr.2013.09.014","article-title":"Low-Dose Irradiation Programs Macrophage Differentiation to an iNOS+\/M1 Phenotype That Orchestrates Effective T Cell Immunotherapy","volume":"24","author":"Klug","year":"2013","journal-title":"Cancer Cell"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"31","DOI":"10.4049\/jimmunol.1601145","article-title":"Intratumoral Delivery of Immunotherapy\u2014Act Locally, Think Globally","volume":"198","author":"Aznar","year":"2017","journal-title":"J. Immunol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1093\/carcin\/bgw007","article-title":"Low Doses of Gamma Irradiation Potentially Modifies Immunosuppressive Tumor Microenvironment by Retuning Tumor-Associated Macrophages: Lesson from Insulinoma","volume":"37","author":"Prakash","year":"2016","journal-title":"Carcinogenesis"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"332","DOI":"10.1016\/j.lungcan.2015.03.013","article-title":"Intratumoral Macrophage Phenotype and CD8+ T Lymphocytes as Potential Tools to Predict Local Tumor Outgrowth at the Intervention Site in Malignant Pleural Mesothelioma","volume":"88","author":"Cornelissen","year":"2015","journal-title":"Lung Cancer"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1128","DOI":"10.1158\/0008-5472.CAN-12-2731","article-title":"Targeting Tumor-Infiltrating Macrophages Decreases Tumor-Initiating Cells, Relieves Immunosuppression, and Improves Chemotherapeutic Responses","volume":"73","author":"Mitchem","year":"2013","journal-title":"Cancer Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"482","DOI":"10.3171\/2020.8.PEDS20561","article-title":"Preclinical efficacy of ribavirin in SHH and group 3 medulloblastoma","volume":"27","author":"Huq","year":"2021","journal-title":"J. Neurosurg. Pediatr."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"5231","DOI":"10.1038\/onc.2017.110","article-title":"Novel MYC-Driven Medulloblastoma Models from Multiple Embryonic Cerebellar Cells","volume":"36","author":"Kawauchi","year":"2017","journal-title":"Oncogene"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1016\/j.ccr.2011.12.021","article-title":"An Animal Model of MYC-Driven Medulloblastoma","volume":"21","author":"Pei","year":"2012","journal-title":"Cancer Cell"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"7525","DOI":"10.1007\/s13277-015-4621-6","article-title":"RIP1 and RIP3 Complex Regulates Radiation-Induced Programmed Necrosis in Glioblastoma","volume":"37","author":"Das","year":"2015","journal-title":"Tumor Biol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"945","DOI":"10.1007\/s00280-018-3684-7","article-title":"Single Agent Efficacy of the HDAC Inhibitor DATS in Preclinical Models of Glioblastoma","volume":"82","author":"Das","year":"2018","journal-title":"Cancer Chemother. Pharmacol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1007\/s11060-013-1165-8","article-title":"Multi-Targeted DATS Prevents Tumor Progression and Promotes Apoptosis in Ectopic Glioblastoma Xenografts in SCID Mice via HDAC Inhibition","volume":"114","author":"Wallace","year":"2013","journal-title":"J. Neurooncol."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Parvar, S.J., Wong, C.I., Lewis, A., Szychot, E., Morris, C.J., Shorthouse, D., and Dziemidowicz, K. (2025). Convection-Enhanced Delivery for Brain Malignancies: Technical Parameters, Formulation Strategies and Clinical Perspectives. Adv. Drug Deliv. Rev., 224.","DOI":"10.1016\/j.addr.2025.115657"}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/18\/12\/1890\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T09:52:23Z","timestamp":1781085143000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/18\/12\/1890"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,10]]},"references-count":32,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2026,6]]}},"alternative-id":["cancers18121890"],"URL":"https:\/\/doi.org\/10.3390\/cancers18121890","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,10]]}}}