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Inhibition of FGFR Reactivates IFNγ Signaling in Tumor Cells to Enhance the Combined Antitumor Activity of Lenvatinib with Anti-PD-1 Antibodies.
Adachi, Yusuke; Kamiyama, Hiroshi; Ichikawa, Kenji; Fukushima, Sayo; Ozawa, Yoichi; Yamaguchi, Shogo; Goda, Satoshi; Kimura, Takayuki; Kodama, Kotaro; Matsuki, Masahiro; Miyano, Saori Watanabe; Yokoi, Akira; Kato, Yu; Funahashi, Yasuhiro.
Affiliation
  • Adachi Y; Tsukuba Research Laboratories, Eisai Co., Ltd., Ibaraki, Japan. y3-adachi@hhc.eisai.co.jp y-funahashi@hhc.eisai.co.jp.
  • Kamiyama H; Tsukuba Research Laboratories, Eisai Co., Ltd., Ibaraki, Japan.
  • Ichikawa K; Tsukuba Research Laboratories, Eisai Co., Ltd., Ibaraki, Japan.
  • Fukushima S; Tsukuba Research Laboratories, Eisai Co., Ltd., Ibaraki, Japan.
  • Ozawa Y; Tsukuba Research Laboratories, Eisai Co., Ltd., Ibaraki, Japan.
  • Yamaguchi S; Tsukuba Research Laboratories, Eisai Co., Ltd., Ibaraki, Japan.
  • Goda S; Tsukuba Research Laboratories, Eisai Co., Ltd., Ibaraki, Japan.
  • Kimura T; Tsukuba Research Laboratories, Eisai Co., Ltd., Ibaraki, Japan.
  • Kodama K; Tsukuba Research Laboratories, Eisai Co., Ltd., Ibaraki, Japan.
  • Matsuki M; Tsukuba Research Laboratories, Eisai Co., Ltd., Ibaraki, Japan.
  • Miyano SW; Tsukuba Research Laboratories, Eisai Co., Ltd., Ibaraki, Japan.
  • Yokoi A; Tsukuba Research Laboratories, Eisai Co., Ltd., Ibaraki, Japan.
  • Kato Y; Tsukuba Research Laboratories, Eisai Co., Ltd., Ibaraki, Japan.
  • Funahashi Y; Tsukuba Research Laboratories, Eisai Co., Ltd., Ibaraki, Japan. y3-adachi@hhc.eisai.co.jp y-funahashi@hhc.eisai.co.jp.
Cancer Res ; 82(2): 292-306, 2022 01 15.
Article in En | MEDLINE | ID: mdl-34753772
Combination therapies consisting of immune checkpoint inhibitors plus anti-VEGF therapy show enhanced antitumor activity and are approved treatments for patients with renal cell carcinoma (RCC). The immunosuppressive roles of VEGF in the tumor microenvironment are well studied, but those of FGF/FGFR signaling remain largely unknown. Lenvatinib is a receptor tyrosine kinase inhibitor that targets both VEGFR and FGFR. Here, we examine the antitumor activity of anti-PD-1 mAb combined with either lenvatinib or axitinib, a VEGFR-selective inhibitor, in RCC. Both combination treatments showed greater antitumor activity and longer survival in mouse models versus either single agent treatment, whereas anti-PD-1 mAb plus lenvatinib had enhanced antitumor activity compared with anti-PD-1 mAb plus axitinib. Flow cytometry analysis showed that lenvatinib decreased the population of tumor-associated macrophages and increased that of IFNγ-positive CD8+ T cells. Activation of FGFR signaling inhibited the IFNγ-stimulated JAK/STAT signaling pathway and decreased expression of its target genes, including B2M, CXCL10, and PD-L1. Furthermore, inhibition of FGFR signaling by lenvatinib restored the tumor response to IFNγ stimulation in mouse and human RCC cell lines. These preclinical results reveal novel roles of tumor FGFR signaling in the regulation of cancer immunity through inhibition of the IFNγ pathway, and the inhibitory activity of lenvatinib against FGFRs likely contributes to the enhanced antitumor activity of combination treatment comprising lenvatinib plus anti-PD-1 mAb. SIGNIFICANCE: FGFR pathway activation inhibits IFNγ signaling in tumor cells, and FGFR inhibition with lenvatinib enhances antitumor immunity and the activity of anti-PD-1 antibodies.
Subject(s)

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Phenylurea Compounds / Quinolines / Carcinoma, Renal Cell / Signal Transduction / Interferon-gamma / Receptors, Fibroblast Growth Factor / Protein Kinase Inhibitors / Programmed Cell Death 1 Receptor / Kidney Neoplasms / Antibodies, Monoclonal Type of study: Prognostic_studies Limits: Animals / Female / Humans Language: En Journal: Cancer Res Year: 2022 Document type: Article Country of publication: United States

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Phenylurea Compounds / Quinolines / Carcinoma, Renal Cell / Signal Transduction / Interferon-gamma / Receptors, Fibroblast Growth Factor / Protein Kinase Inhibitors / Programmed Cell Death 1 Receptor / Kidney Neoplasms / Antibodies, Monoclonal Type of study: Prognostic_studies Limits: Animals / Female / Humans Language: En Journal: Cancer Res Year: 2022 Document type: Article Country of publication: United States