Profiling Fibroblast Growth Factor Receptor 3 Expression Based on the Immune Microenvironment in Upper Tract Urothelial Carcinoma

Keisuke Shigeta; Kazuhiro Matsumoto; Sotaro Kitaoka; Minami Omura; Kota Umeda; Yuki Arita; Shuji Mikami; Keishiro Fukumoto; Yota Yasumizu; Nobuyuki Tanaka; Toshikazu Takeda; Shinya Morita; Takeo Kosaka; Ryuichi Mizuno; Satoshi Hara; Mototsugu Oya

doi:10.1016/j.euo.2024.01.013

Profiling Fibroblast Growth Factor Receptor 3 Expression Based on the Immune Microenvironment in Upper Tract Urothelial Carcinoma

Eur Urol Oncol. 2024 Feb 5:S2588-9311(24)00039-7. doi: 10.1016/j.euo.2024.01.013. Online ahead of print.

Authors

Affiliations

¹ Department of Urology, Keio University School of Medicine, Tokyo, Japan; Department of Urology, Kawasaki Municipal Hospital, Kanagawa, Japan.
² Department of Urology, Keio University School of Medicine, Tokyo, Japan. Electronic address: kazz_matsumoto@yahoo.co.jp.
³ Department of Urology, Kawasaki Municipal Hospital, Kanagawa, Japan.
⁴ Department of Radiology, Keio University School of Medicine, Tokyo, Japan.
⁵ Division of Diagnostic Pathology, Keio University School of Medicine, Tokyo, Japan.
⁶ Department of Urology, Keio University School of Medicine, Tokyo, Japan.

PMID: 38320909
DOI: 10.1016/j.euo.2024.01.013

Abstract

Background: Although several studies have shown favorable outcomes in upper tract urothelial carcinoma (UTUC) with fibroblast growth factor receptor 3 (FGFR3) mutations and/or expression, the relationship between immune cell markers and FGFR3 expression remains unknown.

Objective: To clarify the FGFR3-based immune microenvironment and investigate biomarkers to predict the treatment response to pembrolizumab (Pem) in patients with UTUC.

Design, setting, and participants: We conducted immunohistochemical staining in 214 patients with UTUC. The expression levels of FGFR3, CD4, CD8, CD68, CD163, CD204, and programmed cell death ligand 1 (PD-L1) were examined.

Intervention: All UTUC patients underwent radical nephroureterectomy.

Outcome measurements and statistical analysis: We assessed the relationship between these immune markers and patient prognosis.

Results and limitations: A total of 109 (50.9%) patients showed high FGFR3 expressions and a favorable prognosis compared with the remaining patients. Among the six immune markers, CD8 high expression was an independent favorable factor, whereas CD204 expression was an independent prognostic factor for cancer death. From the FGFR3-based immune clustering, three immune clusters were identified. Cluster A showed low FGFR3 with tumor-associated macrophage-rich components (CD204⁺) followed by a poor prognosis due to a poor response to Pem. Cluster B showed low FGFR3 with an immune hot component (CD8⁺), followed by the most favorable prognosis owing to a good response to Pem. Cluster C showed high FGFR3 expression but an immune cold component, followed by a favorable prognosis due to the high FGFR3 expression, but a poor response was confirmed with Pem.

Conclusions: Although most patients exhibit a poor response to Pem, individuals with low FGFR3 expression and immune hot status may benefit clinically from Pem treatment.

Patient summary: We conducted immunohistochemical staining to evaluate fibroblast growth factor receptor 3 (FGFR3)-related immune microenvironment by evaluating the expressions of CD4, CD8, CD68, CD163, CD204, and PD-L1 in 214 upper tract urothelial carcinoma patients. We identified three distinct immune clusters based on FGFR3 expressions and found that patients with a low FGFR3 expression but immune hot status received the maximum benefit from an immune checkpoint inhibitor.

Keywords: CD204; CD8; Fibroblast growth factor receptor 3; Immune microenvironment; Upper tract urothelial carcinoma.