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FGFR3 Alterations in Bladder Cancer Stimulate Serine Synthesis to Induce Immune-Inert Macrophages That Suppress
Yi Ouyang1,2,3, Ziwei Ou1,2,3, Wenlong Zhong1,2,3
1Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, P.R. China.
Abstract:
FGFR3 alterations are common in patients with bladder cancer. While the FGFR tyrosine kinase inhibitor erdafitinib has been approved as a targeted therapy for patients with FGFR3-altered (aFGFR3) bladder cancer, the response rate remains suboptimal, prompting development of strategies to improve treatment response. Here, we observed an immune-desert tumor microenvironment (TME) phenotype in human aFGFR3 bladder cancer and demonstrated that mutant FGFR3 indirectly induces a "cold" TME in mouse bladder cancer models. Single-cell RNA sequencing revealed the central role of macrophages in inducing the cold TME of aFGFR3 tumors. Macrophages in aFGFR3 tumors exhibited reduced T-cell recruitment and antigen presentation capabilities. Increased serine synthesis in bladder cancer cells that was induced by mutant FGFR3 activated the PI3K/Akt pathway in macrophages, shifting them to an immune-inert phenotype. Targeting PI3K in aFGFR3 tumors with duvelisib achieved promising efficacy by reversing the macrophage phenotype, and combination therapy with duvelisib and erdafitinib demonstrated increased antitumor activity. Overall, these findings reveal the critical role of enhanced serine synthesis efflux from cancer cells with mutant FGFR3 in shifting macrophages to an immune-inert phenotype. Reversing the macrophage phenotype holds promise for enhancing erdafitinib efficacy.
Significance:
Metabolic reprogramming of bladder cancer cells driven by mutant FGFR3 increases serine synthesis that suppresses macrophage immunostimulatory functions to generate an immunosuppressive TME, which can be overcome by targeting PI3K.
Insights
Mutant FGFR3 in bladder cancer creates an immune-cold tumor environment by increasing serine synthesis, which inactivates macrophages. Targeting PI3K with duvelisib reverses this, enhancing erdafitinib treatment efficacy.
Area of Science:
- Oncology
- Cancer Immunology
- Cancer Metabolism
Background:
- FGFR3 alterations are prevalent in bladder cancer.
- Erdafitinib, an FGFR tyrosine kinase inhibitor, is approved for FGFR3-altered (aFGFR3) bladder cancer but has suboptimal response rates.
- Strategies to improve treatment efficacy are needed.
Purpose of the Study:
- To investigate the tumor microenvironment (TME) in aFGFR3 bladder cancer.
- To elucidate the mechanisms by which mutant FGFR3 influences the TME.
- To identify therapeutic strategies to overcome treatment resistance.
Main Methods:
- Analysis of human and mouse bladder cancer models with FGFR3 alterations.
- Single-cell RNA sequencing to characterize the TME.
- Assessment of macrophage function, including T-cell recruitment and antigen presentation.
- Pharmacological targeting of PI3K/Akt pathway with duvelisib.
- Combination therapy with duvelisib and erdafitinib.
Main Results:
- FGFR3 alterations induce an immune-desert (cold) TME.
- Macrophages play a key role in this immunosuppressive TME by impairing T-cell recruitment and antigen presentation.
- Mutant FGFR3-induced serine synthesis activates the PI3K/Akt pathway in macrophages, leading to an immune-inert phenotype.
- Duvelisib treatment reversed the macrophage phenotype and showed promising efficacy.
- Combination therapy with duvelisib and erdafitinib enhanced antitumor activity.
Conclusions:
- Enhanced serine synthesis from FGFR3-mutant bladder cancer cells drives macrophage immunosuppression.
- Reversing macrophage phenotype by targeting PI3K is a viable strategy to improve erdafitinib efficacy in aFGFR3 bladder cancer.
- This study reveals a novel metabolic-immune crosstalk in bladder cancer.
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