FGFR inhibition augments anti-PD-1 efficacy in murine FGFR3-mutant bladder cancer by abrogating immunosuppression
Atsushi Okato1, Takanobu Utsumi1, Michela Ranieri2
1Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina, USA.
Abstract:
The combination of targeted therapy with immune checkpoint inhibition (ICI) is an area of intense interest. We studied the interaction of fibroblast growth factor receptor (FGFR) inhibition with ICI in urothelial carcinoma (UC) of the bladder, in which FGFR3 is altered in 50% of cases. Using an FGFR3-driven, Trp53-mutant genetically engineered murine model (UPFL), we demonstrate that UPFL tumors recapitulate the histology and molecular subtype of their FGFR3-altered human counterparts. Additionally, UPFL1 allografts exhibit hyperprogression to ICI associated with an expansion of T regulatory cells (Tregs). Erdafitinib blocked Treg proliferation in vitro, while in vivo ICI-induced Treg expansion was fully abrogated by FGFR inhibition. Combined erdafitinib and ICI resulted in high therapeutic efficacy. In aggregate, our work establishes that, in mice, co-alteration of FGFR3 and Trp53 results in high-grade, non-muscle-invasive UC and presents a previously underappreciated role for FGFR inhibition in blocking ICI-induced Treg expansion.
Insights
Fibroblast growth factor receptor (FGFR) inhibition combined with immune checkpoint inhibitors (ICI) shows promise in bladder cancer. FGFR inhibition blocks ICI-induced T regulatory cell expansion, leading to high therapeutic efficacy in preclinical models.
Area of Science:
- Oncology
- Immunotherapy
- Molecular Biology
Background:
- The combination of targeted therapy and immune checkpoint inhibition (ICI) is a key area of research in cancer treatment.
- Fibroblast growth factor receptor (FGFR) alterations, particularly FGFR3, are prevalent in urothelial carcinoma (UC) of the bladder.
- Understanding the interaction between FGFR inhibition and ICI is crucial for optimizing treatment strategies.
Purpose of the Study:
- To investigate the synergistic effects of fibroblast growth factor receptor (FGFR) inhibition and immune checkpoint inhibition (ICI) in urothelial carcinoma (UC).
- To elucidate the role of FGFR inhibition in modulating the tumor microenvironment, specifically T regulatory cell (Treg) expansion, during ICI treatment.
Main Methods:
- Utilized an FGFR3-driven, Trp53-mutant genetically engineered murine model (UPFL) for urothelial carcinoma.
- Assessed tumor histology and molecular subtypes, and evaluated response to ICI.
- Investigated the effect of erdafitinib (an FGFR inhibitor) on Treg proliferation in vitro and in vivo, both alone and in combination with ICI.
Main Results:
- UPFL tumors mirrored the characteristics of human FGFR3-altered UC.
- UPFL1 allografts demonstrated hyperprogression to ICI, linked to an increase in T regulatory cells (Tregs).
- FGFR inhibition with erdafitinib effectively blocked Treg proliferation in vitro and abrogated ICI-induced Treg expansion in vivo, leading to significant therapeutic efficacy when combined with ICI.
Conclusions:
- Co-alteration of FGFR3 and Trp53 in mice leads to high-grade, non-muscle-invasive urothelial carcinoma.
- FGFR inhibition plays a critical role in preventing ICI-induced Treg expansion, enhancing the efficacy of combined therapy.
- This study highlights a novel mechanism for FGFR inhibitors in overcoming resistance to immune checkpoint inhibition in bladder cancer.
