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FGFR inhibition augments anti–PD-1 efficacy in murine FGFR3-mutant bladder cancer by abrogating immunosuppression
Atsushi Okato, … , Kwok-Kin Wong, William Y. Kim
Atsushi Okato, … , Kwok-Kin Wong, William Y. Kim
Published January 16, 2024
Citation Information: J Clin Invest. 2024;134(2):e169241. https://doi.org/10.1172/JCI169241.
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Research Article Oncology Article has an altmetric score of 26

FGFR inhibition augments anti–PD-1 efficacy in murine FGFR3-mutant bladder cancer by abrogating immunosuppression

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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.

Authors

Atsushi Okato, Takanobu Utsumi, Michela Ranieri, Xingnan Zheng, Mi Zhou, Luiza D. Pereira, Ting Chen, Yuki Kita, Di Wu, Hyesun Hyun, Hyojin Lee, Andrew S. Gdowski, John D. Raupp, Sean Clark-Garvey, Ujjawal Manocha, Alison Chafitz, Fiona Sherman, Janaye Stephens, Tracy L. Rose, Matthew I. Milowsky, Sara E. Wobker, Jonathan S. Serody, Jeffrey S. Damrauer, Kwok-Kin Wong, William Y. Kim

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Figure 3

FGFR3 promotes a luminal expression pattern and suppresses the basal transcriptional program across all urothelial cell types, but most prominently in luminal cells.

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FGFR3 promotes a luminal expression pattern and suppresses the basal tra...
(A) tSNE plot of scRNA-seq data of combined control (n = 2) and erdafitinib-treated (n = 2) tumors. (B) tSNE plot of scRNA-seq data of epithelial cells of combined control (n = 2) and erdafitinib-treated (n = 2) tumors clustered on basal and luminal genes, demonstrating 3 clusters. (C) Percentage and level of RNA expression of differentially expressed genes across the indicated clusters. (D) Histograms of basal and luminal scores of the indicated clusters from B. (E) Proportion of epithelial cell type (basal, intermediate, luminal) of control or erdafitinib-treated tumors demonstrates expansion of intermediate cells in erdafitinib-treated tumors. (F) Back-to-back violin plots of basal and luminal scores by cell type (basal, intermediate, luminal). (G) Back-to-back violin plots of Krt5 and Upk3a RNA expression by cell type (basal, intermediate, luminal). Two-sided t tests were performed, with the P values shown above the given comparison.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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