Impact of the PD-1/PD-L1 inhibitor SCL-1 on MDA-MB231 tumor growth in a humanized MHC-double knockout NOG mouse model
Abstract Although triple-negative breast cancers are still challenging to treat, the development of novel neoadjuvant chemotherapy combined with immune checkpoint antibodies is promising. Our group developed the small compound-based anti-PD-1/PD-L1 inhibitor SCL-1 and reported its potent anti-tumor...
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Nature Portfolio
2025-07-01
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| Online Access: | https://doi.org/10.1038/s41598-025-12103-6 |
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| author | Tomoatsu Ikeya Tadashi Ashizawa Akari Kanematsu Chie Maeda Akira Iizuka Kazue Yamashita Haruo Miyata Yasufumi Kikuchi Kouji Maruyama Mamoru Ito Ken Yamaguchi Yasuto Akiyama |
| author_facet | Tomoatsu Ikeya Tadashi Ashizawa Akari Kanematsu Chie Maeda Akira Iizuka Kazue Yamashita Haruo Miyata Yasufumi Kikuchi Kouji Maruyama Mamoru Ito Ken Yamaguchi Yasuto Akiyama |
| author_sort | Tomoatsu Ikeya |
| collection | DOAJ |
| description | Abstract Although triple-negative breast cancers are still challenging to treat, the development of novel neoadjuvant chemotherapy combined with immune checkpoint antibodies is promising. Our group developed the small compound-based anti-PD-1/PD-L1 inhibitor SCL-1 and reported its potent anti-tumor effects on various syngeneic mouse tumors. We herein investigated the efficacy of SCL-1 using an in vivo humanized NOG mouse system. We established a humanized mouse system using double major histocompatibility complex-knockout NOG mice transplanted with MDA-MB231 breast cancer cells and HLA-matched human PBMCs. Tumor-infiltrating lymphocytes (TILs) were analyzed using flow cytometry and real-time PCR. An RNA-sequencing analysis (RNA-seq) of SCL-1-treated MDA-MB231 tumors was performed to identify differentially expressed genes. Orally administered SCL-1 exerted potent anti-tumor effects with > 50% reduction in tumor sizes, which were dependent on PD-L1 expression and T-cell infiltration. Its effects were significantly stronger than those of nivolumab or atezolizumab. A TIL analysis revealed effector CD8+ T cells expressing cytotoxic markers and exhausted markers as well as increases in NK cells and B cells. RNA-seq showed the up-regulated expression of tumor-specific long non-coding (lnc) RNAs in SCL-1-treated tumor tissues, some of which exhibited high HLA-binding activity. SCL-1 exerted strong tumor growth inhibitory effects that were mediated by effector T-cell induction inside tumors and the up-regulated expression of lncRNAs as neoantigens leading to CTL activation. The up-regulated expression of lncRNAs in SCL-1-treated MDA-MB231 tumors is a novel result and may be one of the mechanisms responsible for the anti-tumor efficacy of SCL-1. |
| format | Article |
| id | doaj-art-ba7af6d90ca94a888916d5864c8dc56b |
| institution | DOAJ |
| issn | 2045-2322 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj-art-ba7af6d90ca94a888916d5864c8dc56b2025-08-20T03:05:21ZengNature PortfolioScientific Reports2045-23222025-07-0115111110.1038/s41598-025-12103-6Impact of the PD-1/PD-L1 inhibitor SCL-1 on MDA-MB231 tumor growth in a humanized MHC-double knockout NOG mouse modelTomoatsu Ikeya0Tadashi Ashizawa1Akari Kanematsu2Chie Maeda3Akira Iizuka4Kazue Yamashita5Haruo Miyata6Yasufumi Kikuchi7Kouji Maruyama8Mamoru Ito9Ken Yamaguchi10Yasuto Akiyama11Immunotherapy Division, Shizuoka Cancer Center Research InstituteImmunotherapy Division, Shizuoka Cancer Center Research InstituteExperimental Animal Facility, Shizuoka Cancer Center Research InstituteImmunotherapy Division, Shizuoka Cancer Center Research InstituteImmunotherapy Division, Shizuoka Cancer Center Research InstituteImmunotherapy Division, Shizuoka Cancer Center Research InstituteImmunotherapy Division, Shizuoka Cancer Center Research InstituteImmunotherapy Division, Shizuoka Cancer Center Research InstituteExperimental Animal Facility, Shizuoka Cancer Center Research InstituteCentral Institute for Experimental Medicine and Life ScienceOffice of the President Emeritus, Shizuoka Cancer CenterImmunotherapy Division, Shizuoka Cancer Center Research InstituteAbstract Although triple-negative breast cancers are still challenging to treat, the development of novel neoadjuvant chemotherapy combined with immune checkpoint antibodies is promising. Our group developed the small compound-based anti-PD-1/PD-L1 inhibitor SCL-1 and reported its potent anti-tumor effects on various syngeneic mouse tumors. We herein investigated the efficacy of SCL-1 using an in vivo humanized NOG mouse system. We established a humanized mouse system using double major histocompatibility complex-knockout NOG mice transplanted with MDA-MB231 breast cancer cells and HLA-matched human PBMCs. Tumor-infiltrating lymphocytes (TILs) were analyzed using flow cytometry and real-time PCR. An RNA-sequencing analysis (RNA-seq) of SCL-1-treated MDA-MB231 tumors was performed to identify differentially expressed genes. Orally administered SCL-1 exerted potent anti-tumor effects with > 50% reduction in tumor sizes, which were dependent on PD-L1 expression and T-cell infiltration. Its effects were significantly stronger than those of nivolumab or atezolizumab. A TIL analysis revealed effector CD8+ T cells expressing cytotoxic markers and exhausted markers as well as increases in NK cells and B cells. RNA-seq showed the up-regulated expression of tumor-specific long non-coding (lnc) RNAs in SCL-1-treated tumor tissues, some of which exhibited high HLA-binding activity. SCL-1 exerted strong tumor growth inhibitory effects that were mediated by effector T-cell induction inside tumors and the up-regulated expression of lncRNAs as neoantigens leading to CTL activation. The up-regulated expression of lncRNAs in SCL-1-treated MDA-MB231 tumors is a novel result and may be one of the mechanisms responsible for the anti-tumor efficacy of SCL-1.https://doi.org/10.1038/s41598-025-12103-6Immune checkpoint inhibitorPD-1/PD-L1Triple-negative breast cancerNOG mouseHumanized mouse |
| spellingShingle | Tomoatsu Ikeya Tadashi Ashizawa Akari Kanematsu Chie Maeda Akira Iizuka Kazue Yamashita Haruo Miyata Yasufumi Kikuchi Kouji Maruyama Mamoru Ito Ken Yamaguchi Yasuto Akiyama Impact of the PD-1/PD-L1 inhibitor SCL-1 on MDA-MB231 tumor growth in a humanized MHC-double knockout NOG mouse model Scientific Reports Immune checkpoint inhibitor PD-1/PD-L1 Triple-negative breast cancer NOG mouse Humanized mouse |
| title | Impact of the PD-1/PD-L1 inhibitor SCL-1 on MDA-MB231 tumor growth in a humanized MHC-double knockout NOG mouse model |
| title_full | Impact of the PD-1/PD-L1 inhibitor SCL-1 on MDA-MB231 tumor growth in a humanized MHC-double knockout NOG mouse model |
| title_fullStr | Impact of the PD-1/PD-L1 inhibitor SCL-1 on MDA-MB231 tumor growth in a humanized MHC-double knockout NOG mouse model |
| title_full_unstemmed | Impact of the PD-1/PD-L1 inhibitor SCL-1 on MDA-MB231 tumor growth in a humanized MHC-double knockout NOG mouse model |
| title_short | Impact of the PD-1/PD-L1 inhibitor SCL-1 on MDA-MB231 tumor growth in a humanized MHC-double knockout NOG mouse model |
| title_sort | impact of the pd 1 pd l1 inhibitor scl 1 on mda mb231 tumor growth in a humanized mhc double knockout nog mouse model |
| topic | Immune checkpoint inhibitor PD-1/PD-L1 Triple-negative breast cancer NOG mouse Humanized mouse |
| url | https://doi.org/10.1038/s41598-025-12103-6 |
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