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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

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 6

FGFR inhibition enhances the effect of PD-1 blockade.

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FGFR inhibition enhances the effect of PD-1 blockade.
(A) Tumor growth c...
(A) Tumor growth curves of UPFL1 subcutaneous syngeneic tumors treated with the indicated treatments when tumor reached 150 to 300 mm3 in volume. Significance testing was performed by 1-way ANOVA with post hoc Tukey’s HSD. *P < 0.05, **P < 0.001. (B) FFPE tumors were sectioned and dual stained for CD8 and with Masson’s trichrome. Immune phenotyping was performed and the phenotype/CD8 intensity call was plotted as the proportion of each treatment group. Flow cytometry was performed on UPFL1 syngeneic tumors following 1 week of treatment. CTRL, control. (C) Box-and-whisker plots of percentage of cells in each treatment group of CD45+, CD3+, and CD8+ cytotoxic T cells after 1 week of treatment. (D) Box-and-whisker plot of percentage of cells in each treatment group of CD4+ cytotoxic T cells and CTLA-4+ cells after 1 week of treatment. (E) Cell types were assigned to scRNA-seq data from either control or erdafitinib-treated UPFL GEMM tumors using SingleR. The frequency of each immune cell type was plotted as a proportion of all immune cells. The inset percentage represents the percentage of T cells as a proportion of the total immune population. (F) The T cell subset of cells were plotted by the scRNA expression values for Icos, a marker of active/proliferative Tregs. (G) FoxP3+GFP+ cells were isolated from murine spleens and cocultured in the presence or absence of APCs and increasing doses of erdafitinib (n = 3 for each group). (H) Bulk RNA-seq data (GSE135390) from flow-sorted T cells (naive, Th, and Treg) were plotted for FOXP3, FGFR1, FGFR2, and FGFR4. Plots show the IQR and midline at the median. Error bars represent Q1/Q3 ± (1.5 × IQR). Two-sided t tests followed by Bonferroni’s correction to account for multiple comparisons were preformed, with the P values shown above the given comparison.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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