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The Impact of FGFR3 Alterations on the Tumor Microenvironment and the Efficacy of Immune Checkpoint Inhibitors in Bladder Cancer.
Komura, Kazumasa; Hirosuna, Kensuke; Tokushige, Satoshi; Tsujino, Takuya; Nishimura, Kazuki; Ishida, Mitsuaki; Hayashi, Takuo; Ura, Ayako; Ohno, Takaya; Yamazaki, Shogo; Nakamori, Keita; Kinoshita, Shoko; Maenosono, Ryoichi; Ajiro, Masahiko; Yoshikawa, Yuki; Takai, Tomoaki; Tsutsumi, Takeshi; Taniguchi, Kohei; Tanaka, Tomohito; Takahara, Kiyoshi; Konuma, Tsuyoshi; Inamoto, Teruo; Hirose, Yoshinobu; Ono, Fumihito; Shiraishi, Yuichi; Yoshimi, Akihide; Azuma, Haruhito.
Affiliation
  • Komura K; Department of Urology, Osaka Medical and Pharmaceutical University, 2-7 Daigaku-Machi, Takatsuki City, Osaka, 569-8686, Japan. kazumasa.komura@ompu.ac.jp.
  • Hirosuna K; Division of Translational Research, Osaka Medical and Pharmaceutical University, 2-7 Daigaku-Machi, Takatsuki City, Osaka, 569-8686, Japan. kazumasa.komura@ompu.ac.jp.
  • Tokushige S; Division of Translational Research, Osaka Medical and Pharmaceutical University, 2-7 Daigaku-Machi, Takatsuki City, Osaka, 569-8686, Japan.
  • Tsujino T; Department of Regenerative Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-Cho Kitaku, Okayama City, Okayama, 700-8558, Japan.
  • Nishimura K; Department of Urology, Osaka Medical and Pharmaceutical University, 2-7 Daigaku-Machi, Takatsuki City, Osaka, 569-8686, Japan.
  • Ishida M; Department of Urology, Osaka Medical and Pharmaceutical University, 2-7 Daigaku-Machi, Takatsuki City, Osaka, 569-8686, Japan.
  • Hayashi T; Department of Urology, Osaka Medical and Pharmaceutical University, 2-7 Daigaku-Machi, Takatsuki City, Osaka, 569-8686, Japan.
  • Ura A; Division of Cancer RNA Research, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-Ku, Tokyo, 104-0045, Japan.
  • Ohno T; Department of Pathology, Osaka Medical and Pharmaceutical University, 2-7 Daigaku-Machi, Takatsuki City, Osaka, 569-8686, Japan.
  • Yamazaki S; Department of Human Pathology, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-Ku, Tokyo, 113-8421, Japan.
  • Nakamori K; Department of Human Pathology, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-Ku, Tokyo, 113-8421, Japan.
  • Kinoshita S; Department of Urology, Osaka Medical and Pharmaceutical University, 2-7 Daigaku-Machi, Takatsuki City, Osaka, 569-8686, Japan.
  • Maenosono R; Department of Urology, Osaka Medical and Pharmaceutical University, 2-7 Daigaku-Machi, Takatsuki City, Osaka, 569-8686, Japan.
  • Ajiro M; Department of Urology, Osaka Medical and Pharmaceutical University, 2-7 Daigaku-Machi, Takatsuki City, Osaka, 569-8686, Japan.
  • Yoshikawa Y; Department of Urology, Osaka Medical and Pharmaceutical University, 2-7 Daigaku-Machi, Takatsuki City, Osaka, 569-8686, Japan.
  • Takai T; Department of Urology, Osaka Medical and Pharmaceutical University, 2-7 Daigaku-Machi, Takatsuki City, Osaka, 569-8686, Japan.
  • Tsutsumi T; Division of Cancer RNA Research, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-Ku, Tokyo, 104-0045, Japan.
  • Taniguchi K; Division of Cancer RNA Research, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-Ku, Tokyo, 104-0045, Japan.
  • Tanaka T; Department of Urology, Osaka Medical and Pharmaceutical University, 2-7 Daigaku-Machi, Takatsuki City, Osaka, 569-8686, Japan.
  • Takahara K; Department of Urology, Osaka Medical and Pharmaceutical University, 2-7 Daigaku-Machi, Takatsuki City, Osaka, 569-8686, Japan.
  • Konuma T; Department of Urology, Osaka Medical and Pharmaceutical University, 2-7 Daigaku-Machi, Takatsuki City, Osaka, 569-8686, Japan.
  • Inamoto T; Division of Translational Research, Osaka Medical and Pharmaceutical University, 2-7 Daigaku-Machi, Takatsuki City, Osaka, 569-8686, Japan.
  • Hirose Y; Division of Translational Research, Osaka Medical and Pharmaceutical University, 2-7 Daigaku-Machi, Takatsuki City, Osaka, 569-8686, Japan.
  • Ono F; Department of Urology, Fujita-Health University School of Medicine, Toyoake City, 1-98 Dengakugakubo, KutsukakeAichi, 470-1192, Japan.
  • Shiraishi Y; Graduate School of Medical Life Science, Yokohama City University, 1-7-29 Suehiro-Cho, Tsurumiku-Ku, Yokohama, Kanagawa, 230-0045, Japan.
  • Yoshimi A; Department of Urology, Osaka Medical and Pharmaceutical University, 2-7 Daigaku-Machi, Takatsuki City, Osaka, 569-8686, Japan.
  • Azuma H; Department of Pathology, Osaka Medical and Pharmaceutical University, 2-7 Daigaku-Machi, Takatsuki City, Osaka, 569-8686, Japan.
Mol Cancer ; 22(1): 185, 2023 11 18.
Article in En | MEDLINE | ID: mdl-37980528
ABSTRACT

BACKGROUND:

Currently, only limited knowledge is available regarding the phenotypic association between fibroblast growth factor receptor 3 (FGFR3) alterations and the tumor microenvironment (TME) in bladder cancer (BLCA).

METHODS:

A multi-omics analysis on 389 BLCA and 35 adjacent normal tissues from a cohort of OMPU-NCC Consortium Japan was retrospectively performed by integrating the whole-exome and RNA-sequence dataset and clinicopathological record. A median follow-up duration of all BLCA cohort was 31 months.

RESULTS:

FGFR3 alterations (aFGFR3), including recurrent mutations and fusions, accounted for 44% of non-muscle invasive bladder cancer (NMIBC) and 15% of muscle-invasive bladder cancer (MIBC). Within MIBC, the consensus subtypes LumP was significantly more prevalent in aFGFR3, whereas the Ba/Sq subtype exhibited similarity between intact FGFR3 (iFGFR3) and aFGFR3 cases. We revealed that basal markers were significantly increased in MIBC/aFGFR3 compared to MIBC/iFGFR3. Transcriptome analysis highlighted TIM3 as the most upregulated immune-related gene in iFGFR3, with differential immune cell compositions observed between iFGFR3 and aFGFR3. Using EcoTyper, TME heterogeneity was discerned even within aFGFR cases, suggesting potential variations in the response to checkpoint inhibitors (CPIs). Among 72 patients treated with CPIs, the objective response rate (ORR) was comparable between iFGFR3 and aFGFR3 (20% vs 31%; p = 0.467). Strikingly, a significantly higher ORR was noted in LumP/aFGFR3 compared to LumP/iFGFR3 (50% vs 5%; p = 0.022). This trend was validated using data from the IMvigor210 trial. Additionally, several immune-related genes, including IDO1, CCL24, IL1RL1, LGALS4, and NCAM (CD56) were upregulated in LumP/iFGFR3 compared to LumP/aFGFR3 cases.

CONCLUSIONS:

Differential pathways influenced by aFGFR3 were observed between NMIBC and MIBC, highlighting the upregulation of both luminal and basal markers in MIBC/aFGFR3. Heterogeneous TME was identified within MIBC/aFGFR3, leading to differential outcomes for CPIs. Specifically, a favorable ORR in LumP/aFGFR3 and a poor ORR in LumP/iFGFR3 were observed. We propose TIM3 as a potential target for iFGFR3 (ORR 20%) and several immune checkpoint genes, including IDO1 and CCL24, for LumP/iFGFR3 (ORR 5%), indicating promising avenues for precision immunotherapy for BLCA.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Urinary Bladder Neoplasms / Immune Checkpoint Inhibitors Limits: Humans Language: En Journal: Mol Cancer Journal subject: NEOPLASIAS Year: 2023 Document type: Article Affiliation country:
Fulltext
Add to My VHL
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Urinary Bladder Neoplasms / Immune Checkpoint Inhibitors Limits: Humans Language: En Journal: Mol Cancer Journal subject: NEOPLASIAS Year: 2023 Document type: Article Affiliation country: