{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T14:01:43Z","timestamp":1787666503804,"version":"build-2736575974"},"reference-count":18,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2025,5,15]],"date-time":"2025-05-15T00:00:00Z","timestamp":1747267200000},"content-version":"vor","delay-in-days":14,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Cancer Medicine"],"published-print":{"date-parts":[[2025,5]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:sec><jats:title>Purpose<\/jats:title><jats:p>Imiquimod (IQM), an imidazoquinoline derivative, is an immunomodulator that activates an adaptive immune response. IQM is applied topically for genital warts and actinic keratosis. Programmed cell death\u20101 (PD\u20101) suppresses activated T cells by binding to programmed cell death\u2010ligand 1 and programmed cell death\u2010ligand 2, braking antitumor immunity. Anti\u2010PD\u20101 therapy has been used for various malignant neoplasms including renal cell carcinoma (RCC). Whether combination therapy with transcutaneous administration of IQM cream and intraperitoneal administration of anti\u2010PD\u20101 monoclonal antibody (mAb) suppresses mouse RCC cells growing in subcutaneous tissue was investigated.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Female BALB\/c mice were implanted subcutaneously with 2\u2009\u00d7\u200910<jats:sup>5<\/jats:sup> RENCA mouse RCC cells and treated with a transcutaneously applied cream containing IQM and intraperitoneal administration of anti\u2010PD\u20101 mAb beginning 5\u2009days after cell implantation. Tumor burden and survival of the mice were determined. RENCA tumor\u2010specific IgG production and a minor CD8<jats:sup>+<\/jats:sup> T cell subset derived from the spleen of the mice bearing RENCA tumor were detected by flow cytometry. The tumor and spleen weights of mice treated with IQM, anti\u2010PD\u20101 mAb, and their combination were compared.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Combination therapy with IQM and anti\u2010PD\u20101 mAb significantly suppressed tumor growth compared to each monotherapy and prolonged the survival of the mice. The combination therapy produced more RENCA tumor\u2010specific IgG than either IQM or anti\u2010PD\u20101 mAb alone. The percentage of the CD44<jats:sup>high<\/jats:sup>CD62L<jats:sup>low<\/jats:sup> CD8<jats:sup>+<\/jats:sup> T cell subset (effector memory T cells) among splenocytes from mice treated with IQM therapy increased. The CD44<jats:sup>low<\/jats:sup>CD62L<jats:sup>low<\/jats:sup> CD8<jats:sup>+<\/jats:sup> T cell subset (pre\u2010effector\u2010like T cells) of mice treated with anti\u2010PD\u20101 mAb increased. A negative correlation between tumor and spleen weights was suggested in mice treated with therapies containing IQM.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>The present results show that combination therapy with IQM and anti\u2010PD\u20101 mAb might be a promising novel therapeutic strategy for advanced RCC.<\/jats:p><\/jats:sec>","DOI":"10.1002\/cam4.70966","type":"journal-article","created":{"date-parts":[[2025,5,15]],"date-time":"2025-05-15T11:25:43Z","timestamp":1747308343000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Transcutaneous Imiquimod Combined With Anti\u2010Programmed Cell Death\u20101 Monoclonal Antibody Extends the Survival of Mice Bearing Renal Cell Carcinoma"],"prefix":"10.1002","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7338-8059","authenticated-orcid":false,"given":"Takashi","family":"Karashima","sequence":"first","affiliation":[{"name":"Department of Urology Kochi Medical School  Nankoku Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toshihiro","family":"Komatsu","sequence":"additional","affiliation":[{"name":"Department of Immunology Kochi Medical School  Nankoku Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shinkuro","family":"Yamamoto","sequence":"additional","affiliation":[{"name":"Department of Urology Kochi Medical School  Nankoku Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaya","family":"Atagi","sequence":"additional","affiliation":[{"name":"Department of Urology Kochi Medical School  Nankoku Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hatsune","family":"Hashida","sequence":"additional","affiliation":[{"name":"Department of Urology Kochi Medical School  Nankoku Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hideo","family":"Fukuhara","sequence":"additional","affiliation":[{"name":"Department of Urology Kochi Medical School  Nankoku Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenji","family":"Tamura","sequence":"additional","affiliation":[{"name":"Department of Urology Kochi Medical School  Nankoku Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shingo","family":"Ashida","sequence":"additional","affiliation":[{"name":"Department of Urology Kochi Medical School  Nankoku Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taro","family":"Shuin","sequence":"additional","affiliation":[{"name":"Department of Urology Kochi Medical School  Nankoku Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keiko","family":"Udaka","sequence":"additional","affiliation":[{"name":"Department of Immunology Kochi Medical School  Nankoku Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takahiro","family":"Shimizu","sequence":"additional","affiliation":[{"name":"Department Pharmacology Kochi Medical School  Nankoku Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Motoaki","family":"Saito","sequence":"additional","affiliation":[{"name":"Department Pharmacology Kochi Medical School  Nankoku Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nobutaka","family":"Shimizu","sequence":"additional","affiliation":[{"name":"Center for Pelvic Floor Kochi Medical School Hospital  Nankoku Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keiji","family":"Inoue","sequence":"additional","affiliation":[{"name":"Department of Urology Kochi Medical School  Nankoku Japan"},{"name":"Center for Photodynamic Medicine Kochi Medical School Hospital  Nankoku Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,5,15]]},"reference":[{"key":"e_1_2_13_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/cncr.23518"},{"key":"e_1_2_13_3_1","doi-asserted-by":"publisher","DOI":"10.1080\/1744666X.2016.1214575"},{"key":"e_1_2_13_4_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1510665"},{"key":"e_1_2_13_5_1","doi-asserted-by":"publisher","DOI":"10.1097\/00007435-200302000-00006"},{"key":"e_1_2_13_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/ni758"},{"key":"e_1_2_13_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaad.2003.12.010"},{"key":"e_1_2_13_8_1","doi-asserted-by":"publisher","DOI":"10.1067\/mjd.2002.126215"},{"key":"e_1_2_13_9_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.0366-077X.2003.05637.x"},{"key":"e_1_2_13_10_1","doi-asserted-by":"publisher","DOI":"10.3892\/ol.2017.6235"},{"key":"e_1_2_13_11_1","first-page":"43","article-title":"No Title Freedom of Information Applications as an \u2018Evergreening\u2019 Tactic: Secretary, Department of Health and Ageing v iNOVA Pharmaceuticals (Australia) Pty Ltd (2010) 191 FCR 573; [2010]FCA 1442","volume":"19","author":"Vines T. 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