{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T21:45:20Z","timestamp":1790718320427,"version":"4.1.0"},"reference-count":42,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2021,2,14]],"date-time":"2021-02-14T00:00:00Z","timestamp":1613260800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Although Bacillus Calmette Gu\u00e9rin (BCG) remains a mainstay of adjuvant treatment in high-risk, non-muscle-invasive bladder cancer, BCG failure occurs in up to 40% of patients, with radical cystectomy (RC) as the inevitable therapeutic consequence. Current data suggest that PD-L1 immunosuppressive signaling is responsible for BCG failure, supporting the therapeutic rationale of combining checkpoint inhibitors with BCG. To address the immune cascade in 19 RC specimens obtained after BCG failure, we applied a small immunohistochemical (IHC) panel consisting of selected markers (PD-L1, GATA-3, a disintegrin and metalloproteinase (ADAM) proteases, IL-10\/IL-10R). A modified quick score was used for IHC semi-quantification of these markers in tumor cells (TC) and immune cells (IC) within two different regions: muscle-invasive bladder cancer (MIBC) and primary\/concurrent carcinoma in situ (CIS). Contrary to expectation, PD-L1 was consistently low, irrespective of tumor region and cell type. Intriguingly, expression of ADAM17, which has been reported to release membrane-bound PD-L1, was high in both tumor regions and cell types. Moreover, expression of GATA3, IL-10, and IL-10R was also increased, indicative of a generally immunosuppressive tumor microenvironment in BCG failure. ADAM10 expression was associated with advanced tumor disease at RC. Our findings raise the possibility that ADAM proteases may cleave PD-L1 from the surface of bladder TC and possibly also from IC. Therefore, IHC assessment of PD-L1 expression seems to be insufficient and should be supplemented by ADAM10\/17 in patients with BCG failure.<\/jats:p>","DOI":"10.3390\/jcm10040764","type":"journal-article","created":{"date-parts":[[2021,2,14]],"date-time":"2021-02-14T05:54:49Z","timestamp":1613282089000},"page":"764","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Expression of ADAM Proteases in Bladder Cancer Patients with BCG Failure: A Pilot Study"],"prefix":"10.3390","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5286-9048","authenticated-orcid":false,"given":"Renate","family":"Pichler","sequence":"first","affiliation":[{"name":"Department of Urology, Medical University of Innsbruck, 6020 Innsbruck, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea Katharina","family":"Lindner","sequence":"additional","affiliation":[{"name":"Department of Urology, Medical University of Innsbruck, 6020 Innsbruck, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Georg","family":"Sch\u00e4fer","sequence":"additional","affiliation":[{"name":"Department of Pathology, Medical University of Innsbruck, 6020 Innsbruck, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2964-1544","authenticated-orcid":false,"given":"Gennadi","family":"Tulchiner","sequence":"additional","affiliation":[{"name":"Department of Urology, Medical University of Innsbruck, 6020 Innsbruck, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nina","family":"Staudacher","sequence":"additional","affiliation":[{"name":"Department of Urology, Medical University of Innsbruck, 6020 Innsbruck, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Mayr","sequence":"additional","affiliation":[{"name":"Department of Urology, Medical University of Innsbruck, 6020 Innsbruck, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eva","family":"Comperat","sequence":"additional","affiliation":[{"name":"Department of Pathology, Medical University of Vienna, 1090 Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0319-0239","authenticated-orcid":false,"given":"Jacob J.","family":"Orme","sequence":"additional","affiliation":[{"name":"Division of Medical Oncology, Mayo Clinic, Rochester, MN 55902, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gert","family":"Schachtner","sequence":"additional","affiliation":[{"name":"Department of Urology, Medical University of Innsbruck, 6020 Innsbruck, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9940-7326","authenticated-orcid":false,"given":"Martin","family":"Thurnher","sequence":"additional","affiliation":[{"name":"Department of Urology, Medical University of Innsbruck, 6020 Innsbruck, Austria"},{"name":"Immunotherapy Unit, Department of Urology, Medical University of Innsbruck, 6020 Innsbruck, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,2,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1016\/S0022-5347(17)58737-6","article-title":"Intracavitary Bacillus Calmette-Guerin in the treatment of superficial bladder tumors","volume":"116","author":"Morales","year":"1976","journal-title":"J. Urol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1002\/(SICI)1097-0215(19970106)70:1<128::AID-IJC19>3.0.CO;2-H","article-title":"Bacillus Calmette-Gu\u00e9rin mycobacteria stimulate human blood dendritic cells","volume":"70","author":"Thurnher","year":"1997","journal-title":"Int. J. Cancer"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1488","DOI":"10.1097\/00005392-199805000-00021","article-title":"Activation of human dendritic cells by bacillus Calmette-Guerin","volume":"159","author":"Ramoner","year":"1998","journal-title":"J. Urol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1016\/j.cell.2017.11.025","article-title":"Metabolic Induction of Trained Immunity through the Mevalonate Pathway","volume":"172","author":"Bekkering","year":"2018","journal-title":"Cell"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1038\/s41585-020-0346-4","article-title":"Trained immunity as a molecular mechanism for BCG immunotherapy in bladder cancer","volume":"17","author":"Keating","year":"2020","journal-title":"Nat. Rev. Urol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"394","DOI":"10.3389\/fonc.2018.00394","article-title":"Mevalonate Metabolism in Cancer Stemness and Trained Immunity","volume":"8","author":"Gruenbacher","year":"2018","journal-title":"Front. Oncol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1016\/j.cell.2017.12.031","article-title":"BCG Educates Hematopoietic Stem Cells to Generate Protective Innate Immunity against Tuberculosis","volume":"172","author":"Kaufmann","year":"2018","journal-title":"Cell"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"639","DOI":"10.1016\/j.eururo.2019.08.016","article-title":"European Association of Urology Guidelines on Non-muscle-invasive Bladder Cancer (TaT1 and Carcinoma In Situ)\u20142019 Update","volume":"76","author":"Babjuk","year":"2019","journal-title":"Eur. Urol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"790","DOI":"10.1016\/j.eururo.2006.01.017","article-title":"Management of BCG failures in superficial bladder cancer: A review","volume":"49","author":"Witjes","year":"2006","journal-title":"Eur. Urol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1007\/s00262-016-1945-z","article-title":"Intratumoral Th2 predisposition combines with an increased Th1 functional phenotype in clinical response to intravesical BCG in bladder cancer","volume":"66","author":"Pichler","year":"2017","journal-title":"Cancer Immunol. Immunother."},{"key":"ref_11","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_12","doi-asserted-by":"crossref","first-page":"2891","DOI":"10.2147\/OTT.S165840","article-title":"Bacillus Calmette-Guerin and anti-PD-L1 combination therapy boosts immune response against bladder cancer","volume":"11","author":"Wang","year":"2018","journal-title":"Onco Targets Ther."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1499","DOI":"10.1002\/cncr.22588","article-title":"PD-L1 (B7-H1) expression by urothelial carcinoma of the bladder and BCG-induced granulomata: Associations with localized stage progression","volume":"109","author":"Inman","year":"2007","journal-title":"Cancer"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"4800","DOI":"10.1158\/1078-0432.CCR-08-0731","article-title":"T-cell coregulatory molecule expression in urothelial cell carcinoma: Clinicopathologic correlations and association with survival","volume":"14","author":"Boorjian","year":"2008","journal-title":"Clin. Cancer Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"350","DOI":"10.1200\/JCO.2019.37.7_suppl.350","article-title":"Keynote 057: Phase II trial of Pembrolizumab (pembro) for patients (pts) with high-risk (HR) nonmuscle invasive bladder cancer (NMIBC) unresponsive to bacillus calmette-gu\u00e9rin (BCG)","volume":"37","author":"Balar","year":"2019","journal-title":"J. Clin. Oncol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2537","DOI":"10.1007\/s00345-019-03065-2","article-title":"Prognostic significance of pre- and post-treatment PD-L1 expression in patients with primary high-grade non-muscle-invasive bladder cancer treated with BCG immunotherapy","volume":"38","author":"Aydin","year":"2020","journal-title":"World J. Urol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1517","DOI":"10.1007\/s00345-019-02896-3","article-title":"Clinical interest of PD-L1 immuno-histochemistry expression as a predictive factor of Bacillus Calmette Guerin (BCG) efficacy in refractory high-risk non-muscle-invasive bladder cancer (NMIBC)","volume":"38","author":"Delcourt","year":"2020","journal-title":"World J. Urol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1744980","DOI":"10.1080\/2162402X.2020.1744980","article-title":"ADAM10 and ADAM17 cleave PD-L1 to mediate PD-(L)1 inhibitor resistance","volume":"9","author":"Orme","year":"2020","journal-title":"Oncoimmunology"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"466","DOI":"10.1016\/j.eururo.2005.12.031","article-title":"Predicting recurrence and progression in individual patients with stage Ta T1 bladder cancer using EORTC risk tables: A combined analysis of 2596 patients from seven EORTC trials","volume":"49","author":"Sylvester","year":"2006","journal-title":"Eur. Urol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1016\/j.eururo.2018.09.002","article-title":"Genomic Differences Between \u201cPrimary\u201d and \u201cSecondary\u201d Muscle-invasive Bladder Cancer as a Basis for Disparate Outcomes to Cisplatin-based Neoadjuvant Chemotherapy","volume":"75","author":"Pietzak","year":"2019","journal-title":"Eur. Urol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"876","DOI":"10.1136\/jcp.48.9.876","article-title":"A \u201cquickscore\u201d method for immunohistochemical semiquantitation: Validation for oestrogen receptor in breast carcinomas","volume":"48","author":"Detre","year":"1995","journal-title":"J Clin Pathol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"602","DOI":"10.1046\/j.1464-410X.2001.02394.x","article-title":"Evaluation of cellular tumour rejection mechanisms in the peritumoral bladder wall after bacillus Calmette-Gu\u00e9rin treatment","volume":"88","author":"Saint","year":"2001","journal-title":"BJU Int."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1016\/j.eururo.2015.06.023","article-title":"Cytokine Panel for Response to Intravesical Therapy (CyPRIT): Nomogram of Changes in Urinary Cytokine Levels Predicts Patient Response to Bacillus Calmette-Gu\u00e9rin","volume":"69","author":"Kamat","year":"2016","journal-title":"Eur Urol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1007\/s00262-003-0384-9","article-title":"Urinary interleukin-2 may predict clinical outcome of intravesical bacillus Calmette-Gu\u00e9rin immunotherapy for carcinoma in situ of the bladder","volume":"52","author":"Watanabe","year":"2003","journal-title":"Cancer Immunol. Immunother."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1016\/j.eururo.2005.05.004","article-title":"BCG dose reduction by decreasing the instillation frequency: Effects on local Th1\/Th2 cytokine responses in a mouse model","volume":"48","author":"Rooyakkers","year":"2005","journal-title":"Eur. Urol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"S272","DOI":"10.1016\/j.jaci.2009.09.045","article-title":"Immune responses to malignancies","volume":"125","author":"Whiteside","year":"2010","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1016\/j.mam.2008.08.001","article-title":"The ADAM metalloproteinases","volume":"29","author":"Edwards","year":"2008","journal-title":"Mol. Aspects Med."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1111\/j.1349-7006.2007.00434.x","article-title":"ADAMs in cancer cell proliferation and progression","volume":"98","author":"Mochizuki","year":"2007","journal-title":"Cancer Sci."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"745","DOI":"10.1038\/s41577-018-0068-5","article-title":"The emerging role of ADAM metalloproteinases in immunity","volume":"18","author":"Lambrecht","year":"2018","journal-title":"Nat. Rev. Immunol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1281","DOI":"10.1126\/science.282.5392.1281","article-title":"An essential role for ectodomain shedding in mammalian development","volume":"282","author":"Peschon","year":"1998","journal-title":"Science"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"884","DOI":"10.1038\/47260","article-title":"EGF receptor transactivation by G-protein-coupled receptors requires metalloproteinase cleavage of proHB-EGF","volume":"402","author":"Prenzel","year":"1999","journal-title":"Nature"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"871","DOI":"10.1016\/j.cell.2009.11.007","article-title":"Epithelial-mesenchymal transitions in development and disease","volume":"139","author":"Thiery","year":"2009","journal-title":"Cell."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1007\/s10555-009-9194-7","article-title":"Role of epithelial-to-mesenchymal transition (EMT) in drug sensitivity and metastasis in bladder cancer","volume":"28","author":"McConkey","year":"2009","journal-title":"Cancer Metastasis Rev."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"16043","DOI":"10.18632\/oncotarget.24682","article-title":"ADAM17 inhibition enhances platinum efficiency in ovarian cancer","volume":"9","author":"Hedemann","year":"2018","journal-title":"Oncotarget"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"9263","DOI":"10.1007\/s13277-014-2201-9","article-title":"ADAM10 regulates proliferation, invasion, and chemoresistance of bladder cancer cells","volume":"35","author":"Fu","year":"2014","journal-title":"Tumour Biol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"39916","DOI":"10.18632\/oncotarget.9537","article-title":"Tumor-infiltrating immune cell subpopulations influence the oncologic outcome after intravesical Bacillus Calmette-Gu\u00e9rin therapy in bladder cancer","volume":"7","author":"Pichler","year":"2016","journal-title":"Oncotarget"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"2033","DOI":"10.1016\/j.humpath.2012.02.011","article-title":"GATA binding protein 3 is down-regulated in bladder cancer yet strong expression is an independent predictor of poor prognosis in invasive tumor","volume":"43","author":"Miyamoto","year":"2012","journal-title":"Hum Pathol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"482","DOI":"10.1016\/j.trecan.2017.05.001","article-title":"ADAM Metalloprotease-Released Cancer Biomarkers","volume":"3","author":"Herrlich","year":"2017","journal-title":"Trends Cancer"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"102948","DOI":"10.1016\/j.critrevonc.2020.102948","article-title":"Systematic review: Soluble immunological biomarkers in advanced non-small-cell lung cancer (NSCLC)","volume":"153","author":"Mildner","year":"2020","journal-title":"Crit. Rev. Oncol. Hematol."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Tiako Meyo, M., Jouinot, A., Giroux-Leprieur, E., Fabre, E., Wislez, M., Alifano, M., Leroy, K., Boudou-Rouquette, P., Tlemsani, C., and Khoudour, N. (2020). Predictive Value of Soluble PD-1, PD-L1, VEGFA, CD40 Ligand and CD44 for Nivolumab Therapy in Advanced Non-Small Cell Lung Cancer: A Case-Control Study. Cancers, 12.","DOI":"10.3390\/cancers12020473"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"eaan2507","DOI":"10.1126\/science.aan2507","article-title":"A pathology atlas of the human cancer transcriptome","volume":"357","author":"Uhlen","year":"2017","journal-title":"Science"},{"key":"ref_42","unstructured":"(2020, November 05). Available online: https:\/\/www.proteinatlas.org\/ENSG00000151694-ADAM17\/pathology\/urothelial+cancer."}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/10\/4\/764\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:24:00Z","timestamp":1760160240000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/10\/4\/764"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,2,14]]},"references-count":42,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2021,2]]}},"alternative-id":["jcm10040764"],"URL":"https:\/\/doi.org\/10.3390\/jcm10040764","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,2,14]]}}}