Abstract 6049: Fibroblast growth factor receptor modulates IFN-γ response in breast cancer

Abstract FGFR is amplified in 20% of metastatic breast cancer cells (MBCs) where it promotes growth, sustains mesenchymal plasticity, and mediates drug resistance. Systemic inhibition of FGFR kinase activity increases the numbers of CD4+ and CD8+ T-cells and decreases abundance of myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment. These data indicate an immunosuppressive role of FGFR signaling pathway in MBCs. However, a mechanism by which blockade of FGFR kinase activity affects T-cell presence in the tumor is not well understood. T-cells decrease tumor progression by releasing cytokines such as interferon gamma (IFN-γ). IFN-γ binds to its cognate receptor to activate the JAK-STAT1 signaling pathway, promoting immune recognition of cancer cells. Herein, we investigate the signaling cross talk between FGFR-IFN-γ and the resultant pathophysiological effects on cancer cells. We observe that FGFR signaling reduces STAT1 phosphorylation in breast cancer cells. Conversely, inhibiting FGFR kinase activity in murine mammary carcinoma cells leads to increased STAT1 phosphorylation, increased expression of downstream interferon response genes including the T-cell chemoattractants CXCL9 and CXCL10, and increased cell surface expression of major histocompatibility complex I (MHC-I). A key mediator of the FGFR signaling cascade is SH2 containing protein tyrosine phosphatase (SHP-2). Pharmacological inhibition of SHP-2 causes a decrease in in-vivo metastatic burden and an increase in T-cell presence in the tumor. Similar to targeted inhibition of FGFR, blockade of SHP-2 activity also increases STAT1 phosphorylation and expression of IFN-γ response genes. We propose a mechanism in which FGFR mediated activation of SHP-2 dephosphorylates tyrosine 701 of STAT1 thereby tempering anti-tumorigenic effects of IFN-γ. Our findings suggest that increased immunogenicity caused by FGFR pathway inhibition can be leveraged to make tumor cells more susceptible to immune attack and can be used in conjunction with immunotherapy for treatment of MBCs. Citation Format: Marvis Monteiro, Mitchell G. Ayers, Michael K. Wendt. Fibroblast growth factor receptor modulates IFN-γ response in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6049.