{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T11:42:14Z","timestamp":1788176534680,"version":"build-2803163510"},"reference-count":51,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2025,8,13]],"date-time":"2025-08-13T00:00:00Z","timestamp":1755043200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"the Cure Alzheimer\u2019s Disease Fund"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["CIMB"],"abstract":"<jats:p>We found, retrospectively, that BCG therapy in non-muscle invasive bladder cancer (NMIBC) reduces the rate of Alzheimer\u2019s disease. Blockade of the ligand PD-L1 or its checkpoint receptor PD-1 has been shown to improve cognitive function and reduce brain pathology features in a mouse model of Alzheimer\u2019s disease (AD). Given that peripheral blood mononuclear cells (PBMCs) are involved in aging brain pathology and thus represent a potential AD therapeutic target, we analyzed the impact of BCG on the expression of PD-1, PD-L1, and inflammation modulators in PBMCs. Cryopreserved PBMCs pre- and post-BCG-treated six melanoma and six NMIBC patients were repurposed for immunoelectrophoretic analysis of PBMC-extracted proteins. PBMCs, post-BCG treatment in melanoma patients, were harvested only 4 months after the start of treatment (short BCG period), whereas the PBMCs of NMIBC patients were harvested 24 to 52 months after starting the BCG treatment. In melanoma PBMCs, BCG upregulated PD-L1 (p = 0.052) while downregulating PD-1 (insignificantly, p = 0.16). In contrast, in NMIBC patients, BCG downregulated PD-L1 (insignificantly, p = 0.67), while upregulating PD-1 (p = 0.0082). PD-L1 positive correlation with p-IkB (r = 0.7228) under BCG is inverted to that of PD-L1 against IkB (p = \u22120.9491). The difference between these opposite correlations is significant (p = 0.011), indicating that PD-L1 is upregulated early after BCG treatment, in association with p-IKB, which enables inflammation. This association subsided later, and for PD-1, did not occur at the short or long BCG periods. Experiments with a larger number of patients may substantiate the hypothesis that an increase in PD-1 by BCG relative to PD-L1 may protect against AD.<\/jats:p>","DOI":"10.3390\/cimb47080651","type":"journal-article","created":{"date-parts":[[2025,8,13]],"date-time":"2025-08-13T13:30:38Z","timestamp":1755091838000},"page":"651","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["BCG Impact on PD-1\/PD-L1 Expression in Peripheral Immunocytes of Cancer Patients\u2014A Potential Explanation for Its Activity in Preventing Alzheimer\u2019s Disease"],"prefix":"10.3390","volume":"47","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-2730-6395","authenticated-orcid":false,"given":"Benjamin Y.","family":"Klein","sequence":"first","affiliation":[{"name":"Department of Microbiology and Molecular Genetics, Hebrew University Medical School, Jerusalem 9112102, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8815-6488","authenticated-orcid":false,"given":"Ofer N.","family":"Gofrit","sequence":"additional","affiliation":[{"name":"Department of Urology, Hadassah University Medical School, Ein-Karem, Jerusalem 9112001, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charles L.","family":"Greenblatt","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Molecular Genetics, Hebrew University Medical School, Jerusalem 9112102, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"111717","DOI":"10.1016\/j.celrep.2022.111717","article-title":"Interpretable deep learning translation of GWAS and multi-omics findings to identify pathobiology and drug repurposing in Alzheimer\u2019s disease","volume":"41","author":"Xu","year":"2022","journal-title":"Cell Rep."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Gofrit, O.N., Klein, B.Y., Cohen, I.R., Ben-Hur, T., Greenblatt, C.L., and Bercovier, H. (2019). Bacillus Calmette-Guerin (BCG) therapy lowers the incidence of Alzheimer\u2019s disease in bladder cancer patients. PLoS ONE, 14.","DOI":"10.1371\/journal.pone.0224433"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1436","DOI":"10.1093\/gerona\/glab115","article-title":"Lower Risk for Dementia Following Adult Tetanus, Diphtheria, and Pertussis (Tdap) Vaccination","volume":"76","author":"Scherrer","year":"2021","journal-title":"J. Gerontol. A Biol. Sci. Med. Sci."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"e5978","DOI":"10.1002\/gps.5978","article-title":"Could routine vaccinations prevent dementia?","volume":"38","author":"Orrell","year":"2023","journal-title":"Int. J. Geriatr. Psychiatry"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"881","DOI":"10.1111\/eci.12132","article-title":"Training innate immunity: The changing concept of immunological memory in innate host defence","volume":"43","author":"Netea","year":"2013","journal-title":"Eur. J. Clin. Investig."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1540","DOI":"10.1016\/j.vaccine.2021.04.011","article-title":"Epigenetic changes related to glucose metabolism in type 1 diabetes after BCG vaccinations: A vital role for KDM2B","volume":"40","author":"Dias","year":"2022","journal-title":"Vaccine"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1016\/S0166-2236(99)01405-8","article-title":"Innate and adaptive immune responses can be beneficial for CNS repair","volume":"22","author":"Schwartz","year":"1999","journal-title":"Trends Neurosci."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"254","DOI":"10.1126\/science.aai8231","article-title":"Can immunotherapy treat neurodegeneration?","volume":"357","author":"Schwartz","year":"2017","journal-title":"Science"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"794","DOI":"10.1016\/j.it.2020.07.005","article-title":"Immunological Features of Non-neuronal Brain Cells: Implications for Alzheimer\u2019s Disease Immunotherapy","volume":"41","author":"Castellani","year":"2020","journal-title":"Trends Immunol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1007\/s00281-022-00944-6","article-title":"The aging immune system in Alzheimer\u2019s and Parkinson\u2019s diseases","volume":"44","author":"Heavener","year":"2022","journal-title":"Semin. Immunopathol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1397","DOI":"10.4103\/1673-5374.360345","article-title":"Bystanders or not? Microglia and lymphocytes in aging and stroke","volume":"18","author":"Nguyen","year":"2023","journal-title":"Neural Regen. Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"115609","DOI":"10.1016\/j.celrep.2025.115609","article-title":"Clonal hematopoiesis-associated motoric deficits caused by monocyte-derived microglia accumulating in aging mice","volume":"44","author":"Kim","year":"2025","journal-title":"Cell Rep."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2088","DOI":"10.1073\/pnas.0337659100","article-title":"Contribution of transplanted bone marrow cells to Purkinje neurons in human adult brains","volume":"100","author":"Weimann","year":"2003","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"3557","DOI":"10.1073\/pnas.0306431101","article-title":"Human CD34 + cells differentiate into microglia and express recombinant therapeutic protein","volume":"101","author":"Asheuer","year":"2004","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1579","DOI":"10.1084\/jem.20050030","article-title":"Hematopoietic cells maintain hematopoietic fates upon entering the brain","volume":"201","author":"Massengale","year":"2005","journal-title":"J. Exp. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1030","DOI":"10.4161\/epi.25865","article-title":"Distinctive patterns of DNA methylation associated with Parkinson disease: Identification of concordant epigenetic changes in brain and peripheral blood leukocytes","volume":"8","author":"Masliah","year":"2013","journal-title":"Epigenetics"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Klein, B.Y., Gofrit, O.N., and Greenblatt, C.L. (2025). Testing Protein Stress Signals in Peripheral Immunocytes Under the Same Treatment Capable of Decreasing the Incidence of Alzheimer\u2019s Disease in Bladder Cancer Patients. Curr. Issues Mol. Biol., 47.","DOI":"10.3390\/cimb47060392"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"25424823241309664","DOI":"10.1177\/25424823241309664","article-title":"Repurposing peripheral immunocytes of Bacillus Calmette Guerin-vaccinated melanoma patients to reveal preventive Alzheimer\u2019s disease mechanisms, possibly via the unfolded protein response","volume":"9","author":"Klein","year":"2025","journal-title":"J. Alzheimers Dis. Rep."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1038\/nm.4022","article-title":"PD-1 immune checkpoint blockade reduces pathology and improves memory in mouse models of Alzheimer\u2019s disease","volume":"22","author":"Baruch","year":"2016","journal-title":"Nat. Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1038\/s41467-019-08352-5","article-title":"PD-1\/PD-L1 checkpoint blockade harnesses monocyte-derived macrophages to combat cognitive impairment in a tauopathy mouse model","volume":"10","author":"Rosenzweig","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_21","first-page":"60","article-title":"Alzheimer\u2019s disease modification mediated by bone marrow-derived macrophages via a TREM2-independent pathway in mouse model of amyloidosis","volume":"2","author":"Castellani","year":"2022","journal-title":"Nat. Aging"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Falcone, M., and Fousteri, G. (2020). Role of the PD-1\/PD-L1 Dyad in the Maintenance of Pancreatic Immune Tolerance for Prevention of Type 1 Diabetes. Front. Endocrinol., 11.","DOI":"10.3389\/fendo.2020.00569"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1229","DOI":"10.1016\/j.cell.2015.08.016","article-title":"Metabolic Competition in the Tumor Microenvironment Is a Driver of Cancer Progression","volume":"162","author":"Chang","year":"2015","journal-title":"Cell"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1818","DOI":"10.1016\/j.celrep.2017.07.075","article-title":"PDL1 Signals through Conserved Sequence Motifs to Overcome Interferon-Mediated Cytotoxicity","volume":"20","author":"Zuazo","year":"2017","journal-title":"Cell Rep."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1038\/s41392-018-0022-9","article-title":"The intracellular signalosome of PD-L1 in cancer cells","volume":"3","author":"Escors","year":"2018","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1534","DOI":"10.1038\/sj.bjc.6600251","article-title":"Autologous cell vaccine as a post operative adjuvant treatment for high-risk melanoma patients (AJCC stages III and IV). The new American Joint Committee on Cancer","volume":"86","author":"Lotem","year":"2002","journal-title":"Br. J. Cancer"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"8121985","DOI":"10.1155\/2016\/8121985","article-title":"Adjuvant Autologous Melanoma Vaccine for Macroscopic Stage III Disease: Survival, Biomarkers, and Improved Response to CTLA-4 Blockade","volume":"2016","author":"Lotem","year":"2016","journal-title":"J. Immunol. Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1016\/j.canlet.2017.11.014","article-title":"Progress and challenges of predictive biomarkers of anti PD-1\/PD-L1 immunotherapy: A systematic review","volume":"414","author":"Teng","year":"2018","journal-title":"Cancer Lett."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1007\/s11255-023-03812-w","article-title":"Pan-immune-inflammation value as a prognostic tool for overall survival and disease-free survival in non-metastatic muscle-invasive bladder cancer","volume":"56","author":"Kayar","year":"2024","journal-title":"Int. Urol. Nephrol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1046\/j.1440-1681.2000.03200.x","article-title":"Alzheimer\u2019s disease and inflammation: A review of cellular and therapeutic mechanisms","volume":"27","author":"Halliday","year":"2000","journal-title":"Clin. Exp. Pharmacol. Physiol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1038\/s41541-018-0062-8","article-title":"Long-term reduction in hyperglycemia in advanced type 1 diabetes: The value of induced aerobic glycolysis with BCG vaccinations","volume":"3","author":"Kuhtreiber","year":"2018","journal-title":"NPJ Vaccines"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"eabq7240","DOI":"10.1126\/sciadv.abq7240","article-title":"BCG vaccinations drive epigenetic changes to the human T cell receptor: Restored expression in type 1 diabetes","volume":"8","author":"Takahashi","year":"2022","journal-title":"Sci. Adv."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"889","DOI":"10.1111\/ggi.14680","article-title":"Can immunization with BCG delay the onset of Alzheimer\u2019s disease?","volume":"23","author":"Gofrit","year":"2023","journal-title":"Geriatr. Gerontol. Int."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"17590914211018117","DOI":"10.1177\/17590914211018117","article-title":"B and T Lymphocyte Densities Remain Stable With Age in Human Cortex","volume":"13","author":"Berry","year":"2021","journal-title":"ASN Neuro"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2702","DOI":"10.1084\/jem.20181737","article-title":"Targeting neuro-immune communication in neurodegeneration: Challenges and opportunities","volume":"215","author":"Deczkowska","year":"2018","journal-title":"J. Exp. Med."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1083","DOI":"10.1038\/s41590-021-00994-2","article-title":"Immune cell compartmentalization for brain surveillance and protection","volume":"22","author":"Croese","year":"2021","journal-title":"Nat. Immunol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"2470","DOI":"10.1007\/s11064-019-02864-8","article-title":"Enhanced Expression of PD-L1 on Microglia After Surgical Brain Injury Exerts Self-Protection from Inflammation and Promotes Neurological Repair","volume":"44","author":"Chen","year":"2019","journal-title":"Neurochem. Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"21","DOI":"10.31887\/DCNS.2019.21.1\/mschwartz","article-title":"Potential immunotherapy for Alzheimer disease and age-related dementia","volume":"21","author":"Schwartz","year":"2019","journal-title":"Dialogues Clin. Neurosci."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"319","DOI":"10.15698\/cst2019.10.201","article-title":"Inflammation induced PD-L1-specific T cells","volume":"3","author":"Munir","year":"2019","journal-title":"Cell Stress"},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Si, Z., Zhang, S., Yang, X., Ding, N., Xiang, M., Zhu, Q., Mao, Y., Lv, Y., Yu, L., and Shang, H. (2019). The Association Between the Incidence Risk of Peripheral Neuropathy and PD-1\/PD-L1 Inhibitors in the Treatment for Solid Tumor Patients: A Systematic Review and Meta-Analysis. Front. Oncol., 9.","DOI":"10.3389\/fonc.2019.00866"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"17537","DOI":"10.1073\/pnas.1202870109","article-title":"Bacille Calmette-Guerin induces NOD2-dependent nonspecific protection from reinfection via epigenetic reprogramming of monocytes","volume":"109","author":"Kleinnijenhuis","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Keefe, R.C., Takahashi, H., Tran, L., Nelson, K., Ng, N., Kuhtreiber, W.M., and Faustman, D.L. (2021). BCG therapy is associated with long-term, durable induction of Treg signature genes by epigenetic modulation. Sci. Rep., 11.","DOI":"10.1038\/s41598-021-94529-2"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"882","DOI":"10.1158\/1078-0432.CCR-19-1920","article-title":"Adaptive Immune Resistance to Intravesical BCG in Non-Muscle Invasive Bladder Cancer: Implications for Prospective BCG-Unresponsive Trials","volume":"26","author":"Kates","year":"2020","journal-title":"Clin. Cancer Res."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1016\/j.urolonc.2023.10.004","article-title":"Optimizing outcomes for high-risk, non-muscle-invasive bladder cancer: The evolving role of PD-(L)1 inhibition","volume":"41","author":"Bedke","year":"2023","journal-title":"Urol. Oncol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"4968","DOI":"10.1158\/1078-0432.CCR-08-3320","article-title":"Autologous melanoma vaccine induces antitumor and self-reactive immune responses that affect patient survival and depend on MHC class II expression on vaccine cells","volume":"15","author":"Lotem","year":"2009","journal-title":"Clin. Cancer Res."},{"key":"ref_46","first-page":"790","article-title":"Isolation of immunogenic and suppressogenic determinants of the nonimmunogenic YAC tumor and the change in its immunogenic repertoire after in vitro cultivation","volume":"13","author":"Klein","year":"1981","journal-title":"Transplant. Proc."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1874","DOI":"10.4049\/jimmunol.126.5.1874","article-title":"Immunogenicity of subcellular fractions and molecular species of MuLV-induced tumors. II. Stimulation of syngeneic antitumor cell-mediated immune responses by subcellular fractions and molecular species of the Rauscher-virus-induced RBL5 tumor","volume":"126","author":"Kobrin","year":"1981","journal-title":"J. Immunol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1764","DOI":"10.1158\/0008-5472.CAN-12-3507","article-title":"HLA-restricted CTL that are specific for the immune checkpoint ligand PD-L1 occur with high frequency in cancer patients","volume":"73","author":"Munir","year":"2013","journal-title":"Cancer Res."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1097\/CJI.0000000000000090","article-title":"Identification of Programmed Death Ligand 1-derived Peptides Capable of Inducing Cancer-reactive Cytotoxic T Lymphocytes From HLA-A24+ Patients With Renal Cell Carcinoma","volume":"38","author":"Minami","year":"2015","journal-title":"J. Immunother."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1186\/s12967-019-1957-5","article-title":"PD-L1-specific helper T-cells exhibit effective antitumor responses: New strategy of cancer immunotherapy targeting PD-L1 in head and neck squamous cell carcinoma","volume":"17","author":"Ohkuri","year":"2019","journal-title":"J. Transl. Med."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"771","DOI":"10.3233\/JAD-240307","article-title":"Intravesical Bacille Calmette-Guerin (BCG) Vaccine Affects Cognition","volume":"100","author":"Greenblatt","year":"2024","journal-title":"J. Alzheimers Dis."}],"container-title":["Current Issues in Molecular Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1467-3045\/47\/8\/651\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:26:19Z","timestamp":1760034379000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1467-3045\/47\/8\/651"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,13]]},"references-count":51,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2025,8]]}},"alternative-id":["cimb47080651"],"URL":"https:\/\/doi.org\/10.3390\/cimb47080651","relation":{},"ISSN":["1467-3045"],"issn-type":[{"value":"1467-3045","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,8,13]]}}}