Abstract 2671: Sustained inhibition of CSF1R signaling effectively augments antitumor immune responses through inhibiting tumor-associated macrophages

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 novel reagent, FF-10101, exhibits a sustained inhibitory effect against colony stimulating factor 1 receptor by forming a covalent bond and reduces immunosuppressive TAMs in the TME, which leads 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-PD-1 antibody and FF-10101 exhibited a far stronger antitumor effect than either treatment alone. In human cancer specimens, FF-10101 treatment reduced 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. Citation Format: Takahiko Sato, Daisuke Sugiyama, Yasuhiro Kojima, Satomi Hattori, Kazuki Sone, Tomohiro Ishikawa, Yuichi Ishikawa, Takuma Kato, Hitoshi Kiyoi, Hiroyoshi Nishikawa. Sustained inhibition of CSF1R signaling effectively augments antitumor immune responses through inhibiting tumor-associated macrophages abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 2671.