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<p>Although programmed cell death-1 (PD-1) inhibitors have shown promising and durable responses in patients with several types of cancer, many patients show resistance to PD-1 inhibitors. Recent evidence has demonstrated that immunosuppressive cells are induced in tumor microenvironment and inhibit the anti-tumor effects of anti-PD-1 monoclonal antibody (αPD-1 mAb). To investigate whether nintedanib-a multi-tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor, fibroblast growth factor receptor, and platelet-derived growth factor receptor-suppresses immunosuppressive cells and enhances the anti-tumor effects of αPD-1 mAb in preclinical models, flowcytometry, immunohistochemistry, and RNA sequencing of tumor-tissue, tumor-draining lymph nodes, spleens were conducted. RNA sequencing of murine tumor tissues revealed that nintedanib decreased the gene signatures related to myeloid-derived suppressor cells (MDSCs) and cancer-associated fibroblasts (CAFs). Flow cytometry showed that nintedanib significantly decreased the MDSC and CAF percentage in tumor-bearing hosts and increased IFN-ϒ<sup>+</sup>CD4<sup>+</sup> and CD8<sup>+</sup> T cells infiltrating into tumors. Immunohistochemical analysis demonstrated that nintedanib treatment significantly increased the number of CD8<sup>+</sup> T cells in the internal area of the tumor. Adding nintedanib to anti-PD-1 mAb therapy significantly inhibited in vivo tumor progression. These results indicate that nintedanib suppresses MDSCs and CAFs by inhibiting VEGFR-, PDGFR-, and FGFR-mediated signaling, thereby increasing effector T-cell infiltration into tumors and enhancing the anti-tumor effects of αPD-1 mAb therapy.</p>

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Nintedanib enhances the antitumor efficacy of pd-1 blockade, potentially through inhibition of myeloid-derived suppressor cells and cancer-associated fibroblasts

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月5日

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  • Ryo Suzuki,
  • Satoshi Watanabe,
  • Kunihiro Shono,
  • Takaaki Masuda,
  • Kensuke Yanai,
  • Ryo Yamazaki,
  • Yumi Ando,
  • Tomoya Wakabayashi,
  • Susumu Tanaka,
  • Tomoki Sekiya,
  • Kohei Kushiro,
  • Naohiro Yanagimura,
  • Miyuki Sato,
  • Tomohiro Tanaka,
  • Koichiro Nozaki,
  • Yu Saida,
  • Satoshi Hokari,
  • Masashi Arita,
  • Riuko Ohashi,
  • Kenjiro Shima,
  • Yosuke Kimura,
  • Nobumasa Aoki,
  • Yasuyoshi Ohshima,
  • Toshiyuki Koya,
  • Toshiaki Kikuchi

摘要

Although programmed cell death-1 (PD-1) inhibitors have shown promising and durable responses in patients with several types of cancer, many patients show resistance to PD-1 inhibitors. Recent evidence has demonstrated that immunosuppressive cells are induced in tumor microenvironment and inhibit the anti-tumor effects of anti-PD-1 monoclonal antibody (αPD-1 mAb). To investigate whether nintedanib-a multi-tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor, fibroblast growth factor receptor, and platelet-derived growth factor receptor-suppresses immunosuppressive cells and enhances the anti-tumor effects of αPD-1 mAb in preclinical models, flowcytometry, immunohistochemistry, and RNA sequencing of tumor-tissue, tumor-draining lymph nodes, spleens were conducted. RNA sequencing of murine tumor tissues revealed that nintedanib decreased the gene signatures related to myeloid-derived suppressor cells (MDSCs) and cancer-associated fibroblasts (CAFs). Flow cytometry showed that nintedanib significantly decreased the MDSC and CAF percentage in tumor-bearing hosts and increased IFN-ϒ+CD4+ and CD8+ T cells infiltrating into tumors. Immunohistochemical analysis demonstrated that nintedanib treatment significantly increased the number of CD8+ T cells in the internal area of the tumor. Adding nintedanib to anti-PD-1 mAb therapy significantly inhibited in vivo tumor progression. These results indicate that nintedanib suppresses MDSCs and CAFs by inhibiting VEGFR-, PDGFR-, and FGFR-mediated signaling, thereby increasing effector T-cell infiltration into tumors and enhancing the anti-tumor effects of αPD-1 mAb therapy.