2. Academic Validation
  3. Sustained inhibition of CSF1R signaling augments antitumor immunity through inhibiting tumor-associated macrophages

Sustained inhibition of CSF1R signaling augments antitumor immunity through inhibiting tumor-associated macrophages

  • JCI Insight. 2025 Jan 9;10(1):e178146. doi: 10.1172/jci.insight.178146.
Takahiko Sato 1 2,  Daisuke Sugiyama 1,  Jun Koseki 3,  Yasuhiro Kojima 4,  Satomi Hattori 1 5,  Kazuki Sone 1,  Hitomi Nishinakamura 6,  Tomohiro Ishikawa 1,  Yuichi Ishikawa 2,  Takuma Kato 1,  Hitoshi Kiyoi 2,  Hiroyoshi Nishikawa 1 6 7 8
Affiliations

Affiliations

  • 1 Department of Immunology and.
  • 2 Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
  • 3 Cellular and Molecular Biotechnology Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), Tokyo, Japan.
  • 4 Laboratory of Computational Life Science, National Cancer Center, Tokyo, Japan.
  • 5 Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
  • 6 Division of Cancer Immunology, Research Institute / Exploratory Oncology Research & Clinical Trial Center (EPOC), National Cancer Center, Tokyo, Japan.
  • 7 Division of Cancer Immune Multicellular System Regulation, Center for Cancer Immunotherapy and Immunobiology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
  • 8 Kindai University Faculty of Medicine, Osaka-sayama, Japan.
PMID: 39782686 DOI: 10.1172/jci.insight.178146
Abstract

Tumor-associated macrophages (TAMs) are one of the key immunosuppressive components in the tumor microenvironment (TME) and contribute to tumor development, progression, and resistance to Cancer Immunotherapy. Several reagents targeting TAMs have been tested in preclinical and clinical studies, but they have had limited success. Here, we show that a unique reagent, FF-10101, exhibited a sustained inhibitory effect against colony-stimulating factor 1 receptor by forming a covalent bond and reduced immunosuppressive TAMs in the TME, which led to strong antitumor immunity. In preclinical animal models, FF-10101 treatment significantly reduced immunosuppressive TAMs and increased antitumor TAMs in the TME. In addition, tumor antigen-specific CD8+ T cells were increased; consequently, tumor growth was significantly inhibited. Moreover, combination treatment with an anti-programmed cell death 1 (anti-PD-1) antibody and FF-10101 exhibited a far stronger antitumor effect than either treatment alone. In human Cancer specimens, FF-10101 treatment reduced programmed cell death 1 ligand 1 (PD-L1) expression on TAMs, as observed in animal models. Thus, FF-10101 acts as an immunomodulatory agent that can reduce immunosuppressive TAMs and augment tumor antigen-specific T cell responses, thereby generating an immunostimulatory TME. We propose that FF-10101 is a potential candidate for successful combination Cancer Immunotherapy with Immune Checkpoint inhibitors, such as PD-1/PD-L1 blockade.

Keywords

Immunology; Macrophages.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-12768
    99.83%, CSF-1R Inhibitor