FGFR inhibition augments anti-PD-1 efficacy in murine FGFR3-mutant bladder cancer by abrogating immunosuppression.
J Clin Invest
; 134(2)2024 Jan 16.
Article
em En
| MEDLINE
| ID: mdl-38226620
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.
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Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Neoplasias da Bexiga Urinária
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Carcinoma de Células de Transição
Tipo de estudo:
Prognostic_studies
Limite:
Animals
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Humans
Idioma:
En
Ano de publicação:
2024
Tipo de documento:
Article