Scholarlink

<p>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 &gt; 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<sup>+</sup> 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.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Impact of the PD-1/PD-L1 inhibitor SCL-1 on MDA-MB231 tumor growth in a humanized MHC-double knockout NOG mouse model

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年7月24日

查看全文
  • Tomoatsu Ikeya,
  • Tadashi Ashizawa,
  • Akari Kanematsu,
  • Chie Maeda,
  • Akira Iizuka,
  • Kazue Yamashita,
  • Haruo Miyata,
  • Yasufumi Kikuchi,
  • Kouji Maruyama,
  • Mamoru Ito,
  • Ken Yamaguchi,
  • Yasuto Akiyama

摘要

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.