Transcutaneous Imiquimod Combined With Anti‐Programmed Cell Death‐1 Monoclonal Antibody Extends the Survival of Mice Bearing Renal Cell Carcinoma
ABSTRACT Purpose 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‐1 (PD‐1) suppresses activated T cells by binding to programmed cell death‐ligand...
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| Format: | Article |
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Wiley
2025-05-01
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| Series: | Cancer Medicine |
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| Online Access: | https://doi.org/10.1002/cam4.70966 |
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| author | Takashi Karashima Toshihiro Komatsu Shinkuro Yamamoto Kaya Atagi Hatsune Hashida Hideo Fukuhara Kenji Tamura Shingo Ashida Taro Shuin Keiko Udaka Takahiro Shimizu Motoaki Saito Nobutaka Shimizu Keiji Inoue |
| author_facet | Takashi Karashima Toshihiro Komatsu Shinkuro Yamamoto Kaya Atagi Hatsune Hashida Hideo Fukuhara Kenji Tamura Shingo Ashida Taro Shuin Keiko Udaka Takahiro Shimizu Motoaki Saito Nobutaka Shimizu Keiji Inoue |
| author_sort | Takashi Karashima |
| collection | DOAJ |
| description | ABSTRACT Purpose 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‐1 (PD‐1) suppresses activated T cells by binding to programmed cell death‐ligand 1 and programmed cell death‐ligand 2, braking antitumor immunity. Anti‐PD‐1 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‐PD‐1 monoclonal antibody (mAb) suppresses mouse RCC cells growing in subcutaneous tissue was investigated. Methods Female BALB/c mice were implanted subcutaneously with 2 × 105 RENCA mouse RCC cells and treated with a transcutaneously applied cream containing IQM and intraperitoneal administration of anti‐PD‐1 mAb beginning 5 days after cell implantation. Tumor burden and survival of the mice were determined. RENCA tumor‐specific IgG production and a minor CD8+ 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‐PD‐1 mAb, and their combination were compared. Results Combination therapy with IQM and anti‐PD‐1 mAb significantly suppressed tumor growth compared to each monotherapy and prolonged the survival of the mice. The combination therapy produced more RENCA tumor‐specific IgG than either IQM or anti‐PD‐1 mAb alone. The percentage of the CD44highCD62Llow CD8+ T cell subset (effector memory T cells) among splenocytes from mice treated with IQM therapy increased. The CD44lowCD62Llow CD8+ T cell subset (pre‐effector‐like T cells) of mice treated with anti‐PD‐1 mAb increased. A negative correlation between tumor and spleen weights was suggested in mice treated with therapies containing IQM. Conclusions The present results show that combination therapy with IQM and anti‐PD‐1 mAb might be a promising novel therapeutic strategy for advanced RCC. |
| format | Article |
| id | doaj-art-2d2832bd214642a69e86c618ac43e7b1 |
| institution | DOAJ |
| issn | 2045-7634 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Wiley |
| record_format | Article |
| series | Cancer Medicine |
| spelling | doaj-art-2d2832bd214642a69e86c618ac43e7b12025-08-20T03:05:29ZengWileyCancer Medicine2045-76342025-05-011410n/an/a10.1002/cam4.70966Transcutaneous Imiquimod Combined With Anti‐Programmed Cell Death‐1 Monoclonal Antibody Extends the Survival of Mice Bearing Renal Cell CarcinomaTakashi Karashima0Toshihiro Komatsu1Shinkuro Yamamoto2Kaya Atagi3Hatsune Hashida4Hideo Fukuhara5Kenji Tamura6Shingo Ashida7Taro Shuin8Keiko Udaka9Takahiro Shimizu10Motoaki Saito11Nobutaka Shimizu12Keiji Inoue13Department of Urology Kochi Medical School Nankoku JapanDepartment of Immunology Kochi Medical School Nankoku JapanDepartment of Urology Kochi Medical School Nankoku JapanDepartment of Urology Kochi Medical School Nankoku JapanDepartment of Urology Kochi Medical School Nankoku JapanDepartment of Urology Kochi Medical School Nankoku JapanDepartment of Urology Kochi Medical School Nankoku JapanDepartment of Urology Kochi Medical School Nankoku JapanDepartment of Urology Kochi Medical School Nankoku JapanDepartment of Immunology Kochi Medical School Nankoku JapanDepartment Pharmacology Kochi Medical School Nankoku JapanDepartment Pharmacology Kochi Medical School Nankoku JapanCenter for Pelvic Floor Kochi Medical School Hospital Nankoku JapanDepartment of Urology Kochi Medical School Nankoku JapanABSTRACT Purpose 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‐1 (PD‐1) suppresses activated T cells by binding to programmed cell death‐ligand 1 and programmed cell death‐ligand 2, braking antitumor immunity. Anti‐PD‐1 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‐PD‐1 monoclonal antibody (mAb) suppresses mouse RCC cells growing in subcutaneous tissue was investigated. Methods Female BALB/c mice were implanted subcutaneously with 2 × 105 RENCA mouse RCC cells and treated with a transcutaneously applied cream containing IQM and intraperitoneal administration of anti‐PD‐1 mAb beginning 5 days after cell implantation. Tumor burden and survival of the mice were determined. RENCA tumor‐specific IgG production and a minor CD8+ 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‐PD‐1 mAb, and their combination were compared. Results Combination therapy with IQM and anti‐PD‐1 mAb significantly suppressed tumor growth compared to each monotherapy and prolonged the survival of the mice. The combination therapy produced more RENCA tumor‐specific IgG than either IQM or anti‐PD‐1 mAb alone. The percentage of the CD44highCD62Llow CD8+ T cell subset (effector memory T cells) among splenocytes from mice treated with IQM therapy increased. The CD44lowCD62Llow CD8+ T cell subset (pre‐effector‐like T cells) of mice treated with anti‐PD‐1 mAb increased. A negative correlation between tumor and spleen weights was suggested in mice treated with therapies containing IQM. Conclusions The present results show that combination therapy with IQM and anti‐PD‐1 mAb might be a promising novel therapeutic strategy for advanced RCC.https://doi.org/10.1002/cam4.70966IgGimiquimodimmune checkpoint inhibitorprogrammed cell death‐1renal cell carcinomaspleen |
| spellingShingle | Takashi Karashima Toshihiro Komatsu Shinkuro Yamamoto Kaya Atagi Hatsune Hashida Hideo Fukuhara Kenji Tamura Shingo Ashida Taro Shuin Keiko Udaka Takahiro Shimizu Motoaki Saito Nobutaka Shimizu Keiji Inoue Transcutaneous Imiquimod Combined With Anti‐Programmed Cell Death‐1 Monoclonal Antibody Extends the Survival of Mice Bearing Renal Cell Carcinoma Cancer Medicine IgG imiquimod immune checkpoint inhibitor programmed cell death‐1 renal cell carcinoma spleen |
| title | Transcutaneous Imiquimod Combined With Anti‐Programmed Cell Death‐1 Monoclonal Antibody Extends the Survival of Mice Bearing Renal Cell Carcinoma |
| title_full | Transcutaneous Imiquimod Combined With Anti‐Programmed Cell Death‐1 Monoclonal Antibody Extends the Survival of Mice Bearing Renal Cell Carcinoma |
| title_fullStr | Transcutaneous Imiquimod Combined With Anti‐Programmed Cell Death‐1 Monoclonal Antibody Extends the Survival of Mice Bearing Renal Cell Carcinoma |
| title_full_unstemmed | Transcutaneous Imiquimod Combined With Anti‐Programmed Cell Death‐1 Monoclonal Antibody Extends the Survival of Mice Bearing Renal Cell Carcinoma |
| title_short | Transcutaneous Imiquimod Combined With Anti‐Programmed Cell Death‐1 Monoclonal Antibody Extends the Survival of Mice Bearing Renal Cell Carcinoma |
| title_sort | transcutaneous imiquimod combined with anti programmed cell death 1 monoclonal antibody extends the survival of mice bearing renal cell carcinoma |
| topic | IgG imiquimod immune checkpoint inhibitor programmed cell death‐1 renal cell carcinoma spleen |
| url | https://doi.org/10.1002/cam4.70966 |
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