Unleashing the potential of combining FGFR inhibitor and immune checkpoint blockade for FGF/FGFR signaling in tumor microenvironment

Abstract

Background: Fibroblast growth factors (FGFs) and their receptors (FGFRs) play a crucial role in cell fate and angiogenesis, with dysregulation of the signaling axis driving tumorigenesis. Therefore, many studies have targeted FGF/FGFR signaling for cancer therapy and several FGFR inhibitors have promising results in different tumors but treatment efficiency may still be improved. The clinical use of immune checkpoint blockade (ICB) has resulted in sustained remission for patients. MAIN: Although there is limited data linking FGFR inhibitors and immunotherapy, preclinical research suggest that FGF/FGFR signaling is involved in regulating the tumor microenvironment (TME) including immune cells, vasculogenesis, and epithelial-mesenchymal transition (EMT). This raises the possibility that ICB in combination with FGFR-tyrosine kinase inhibitors (FGFR-TKIs) may be feasible for treatment option for patients with dysregulated FGF/FGFR signaling.

Conclusion: Here, we review the role of FGF/FGFR signaling in TME regulation and the potential mechanisms of FGFR-TKI in combination with ICB. In addition, we review clinical data surrounding ICB alone or in combination with FGFR-TKI for the treatment of FGFR-dysregulated tumors, highlighting that FGFR inhibitors may sensitize the response to ICB by impacting various stages of the "cancer-immune cycle".

Keywords: Fibroblast growth factor receptor; Immune checkpoint blockade; Immunotherapy; Tumor microenvironment.

Fig. 1

FGFR signaling network. Upon ligand-receptor binding, activation regions are mutually transphosphorylated, leading to the docking of junctional proteins and activation of four key downstream pathways: RAS/RAF/MAPK, PI3K/AKT, PLCγ, and STAT (orange). PIP₂, phosphatidylinositol-4,5-bisphosphate; IP₃, inositol triphosphate; PLCγ, phospholipase C gamma; DAG, diacylglycerol; PKC, protein kinase C; FRS2α, FGFR substrate 2α; GRB2, growth factor receptor-bound 2; GAB1, GRB2-associated binder-1; SoS, son of sevenless; P, phosphorylation; JAK, Janus kinase; PI3K, phosphatidylinositol 3-kinase; STAT, signal transducer and activator of transcription; AKT, protein kinase B; MAPK, mitogen-activated protein kinase

Fig. 2

Effects of FGFR signaling on the TME. a.| FGF/FGFR promotes PD-1 expression and reduces IFNy and GZMB secretion by effector T cells, resulting in a decrease in anti-tumor immunity of T-cells. b.| FGF/FGFR promotes Treg cell survival by assisting IL-2-mediated STAT5 phosphorylation. FGF also promotes the M2-type polarization of TAMs. These functions of FGF/FGFR enhance immunosuppressive effects. c.| FGF/FGFR signaling directly inhibits MHC II expression via the RAS/MAPK pathway. At the same time, FGF/FGFR signaling also inhibited interferon-mediated expression of MHC I and PD-L1 and secretion of CXCL10 via SOSC1. In addition, FGF/FGFR signaling promotes PD-L1 expression through the JAK/STAT pathway and initiates PD-L1 transcription through the upregulation of YAP. d.| On the one hand, FGFR4 reduces PD-L1 degradation by promoting GSK3β phosphorylation at the Ser 9 site. On the other hand, FGFR1 promotes the degradation of ubiquitinated PD-L1 by promoting NEDD4 phosphorylation. IFN-y, interferon-γ; GZMB, granzyme B; TAM, tumor-associated macrophage; MHC, major histocompatibility complex; PD-L1, SOSC1, suppressor of cytokine signaling 1; GSK3β, glycogen synthase kinase 3 beta

Fig. 3

Effects of FGFR signaling on the vascular system. On the one hand, TGF-β facilitates the heterodimeric conversion of FGFR to promote EMT. On the other hand, FGF/FGFR signaling blocks TGF-β activation via let-7 miRNA and Smad2 activation via RAS/MAPK signaling, thus preventing EMT in endothelial cells. FGF promotes endothelial cell adhesion and tight junctions through the coupling of p120-cadherin and VE-cadherin and stimulates matrix metalloproteinase 2 (MMP2) and MMP9 shedding from the cell surface, leading to ECM degradation and promoting angiogenesis. FGF/FGFR also controls the expression of the glycolytic enzyme hexokinase 2 (HK2) via c-MYC, which assists in the metabolism, proliferation and migration of vascular endothelial cells. FGF is involved in the inhibition of expression and secretion of endothelial VCAM1, E-selectin, and ICAM1, which in turn impairs T-cell homing and recruitment. TGF-β, transforming growth factor beta; EMT, epithelial-mesenchymal transition; VCAM1, vascular cell adhesion molecule 1; ICAM1, intercellular cell adhesion molecule 1; ECM, extracellular matrix

Fig. 4

Targeting FGF/FGFR signaling to regulate the cancer-immunity cycle in multiple steps