The Impact of FGFR3 Alterations on the Tumor Microenvironment and the Efficacy of Immune Checkpoint Inhibitors in Bladder Cancer

• DOI: 10.1186/s12943-023-01897-6
• Publication Date: 2023-11-18T11:02:44Z
• Authors: Kazumasa Komura; Kensuke Hirosuna; Satoshi Tokushige; Takuya Tsujino; Kazuki Nishimura; Mitsuaki Ishida; Takuo Hayashi; Ayako Ura; Takaya Ohno; Shogo Yamazaki; Keita Nakamori; Shoko Kinoshita; Ryoichi Maenosono; Masahiko Ajiro; Yuki Yoshikawa; Tomoaki Takai; Takeshi Tsutsumi; Kohei Taniguchi; Tomohito Tanaka; Kiyoshi Takahara; Tsuyoshi Konuma; Teruo Inamoto; Yoshinobu Hirose; Fumihito Ono; Yuichi Shiraishi; Akihide Yoshimi; Haruhito Azuma
• Keywords: Immune checkpoint; Exome

Abstract Background Currently, only limited knowledge is available regarding the phenotypic association between fibroblast growth factor receptor 3 (FGFR3) alterations and tumor microenvironment (TME) in bladder cancer (BLCA). Methods A multi-omics analysis on 389 BLCA 35 adjacent normal tissues from a cohort of OMPU-NCC Consortium Japan was retrospectively performed by integrating whole-exome RNA-sequence dataset clinicopathological record. median follow-up duration all 31 months. Results FGFR3 (aFGFR3), including recurrent mutations fusions, accounted for 44% non-muscle invasive (NMIBC) 15% muscle-invasive (MIBC). Within MIBC, consensus subtypes LumP significantly more prevalent aFGFR3, whereas Ba/Sq subtype exhibited similarity intact (iFGFR3) aFGFR3 cases. We revealed that basal markers were increased MIBC/aFGFR3 compared to MIBC/iFGFR3. Transcriptome highlighted TIM3 as most upregulated immune-related gene iFGFR3, with differential immune cell compositions observed iFGFR3 aFGFR3. Using EcoTyper, TME heterogeneity discerned even within aFGFR cases, suggesting potential variations response checkpoint inhibitors (CPIs). Among 72 patients treated CPIs, objective rate (ORR) comparable (20% vs 31%; p = 0.467). Strikingly, higher ORR noted LumP/aFGFR3 LumP/iFGFR3 (50% 5%; 0.022). This trend validated using data IMvigor210 trial. Additionally, several genes, IDO1, CCL24, IL1RL1, LGALS4, NCAM (CD56) Conclusions Differential pathways influenced NMIBC highlighting upregulation both luminal MIBC/aFGFR3. Heterogeneous identified MIBC/aFGFR3, leading outcomes CPIs. Specifically, favorable poor observed. propose target (ORR: 20%) IDO1 5%), indicating promising avenues precision immunotherapy BLCA.