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

被引：19

作者：

Komura, Kazumasa ^{[1
,2
]}

Hirosuna, Kensuke ^{[2
,3
]}

Tokushige, Satoshi ^{[1
]}

Tsujino, Takuya ^{[1
]}

Nishimura, Kazuki ^{[1
,4
]}

Ishida, Mitsuaki ^{[5
]}

Hayashi, Takuo ^{[6
]}

Ura, Ayako ^{[6
]}

Ohno, Takaya ^{[1
]}

Yamazaki, Shogo ^{[1
]}

Nakamori, Keita ^{[1
]}

Kinoshita, Shoko ^{[1
]}

Maenosono, Ryoichi ^{[1
,4
]}

Ajiro, Masahiko ^{[4
]}

Yoshikawa, Yuki ^{[1
]}

Takai, Tomoaki ^{[1
]}

Tsutsumi, Takeshi ^{[1
]}

Taniguchi, Kohei ^{[2
]}

Tanaka, Tomohito ^{[2
]}

Takahara, Kiyoshi ^{[7
]}

Konuma, Tsuyoshi ^{[8
]}

Inamoto, Teruo ^{[1
]}

Hirose, Yoshinobu ^{[5
]}

Ono, Fumihito ^{[2
]}

Shiraishi, Yuichi ^{[9
]}

Yoshimi, Akihide ^{[4
]}

Azuma, Haruhito ^{[1
]}

机构：

[1] Osaka Med & Pharmaceut Univ, Dept Urol, 2-7 Daigaku Machi, Takatsuki, Osaka 5698686, Japan

[2] Osaka Med & Pharmaceut Univ, Dept Translat Res, 2-7 Daigaku Machi, Takatsuki, Osaka 5698686, Japan

[3] Okayama Univ, Dept Regenerat Sci, Grad Sch Med Dent & Pharmaceut Sci, 2-5-1 Shikata Cho Kitaku, Okayama, Okayama 7008558, Japan

[4] Natl Canc Ctr, Div Canc RNA Res, Res Inst, 5-1-1 Tsukiji,Chuo Ku, Tokyo 1040045, Japan

[5] Osaka Med & Pharmaceut Univ, Dept Pathol, 2-7 Daigaku Machi, Takatsuki, Osaka 5698686, Japan

[6] Juntendo Univ, Grad Sch Med, Dept Human Pathol, 2-1-1 Hongo,Bunkyo Ku, Tokyo 1138421, Japan

[7] Fujita Hlth Univ, Sch Med, Dept Urol, 1-98 Dengakugakubo, Toyoake, Aichi 4701192, Japan

[8] Yokohama City Univ, Grad Sch Med Life Sci, 1-7-29 Suehiro Cho,Tsurumiku Ku, Yokohama, Kanagawa 2300045, Japan

[9] Natl Canc Ctr, Div Genome Anal Platform Dev, Res Inst, 5-1-1 Tsukiji,Chuo Ku, Tokyo 1040045, Japan

来源：

MOLECULAR CANCER | 2023年 / 22卷 / 01期

基金：

日本学术振兴会;

关键词：

Bladder cancer; Fibroblast growth factor receptor; Mutation; Fusion; Tumor microenvironment; Immune checkpoint inhibitor; Molecular subtypes; SINGLE-ARM; PEMBROLIZUMAB; MULTICENTER; NIVOLUMAB; THERAPY;

D O I：

10.1186/s12943-023-01897-6

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

BackgroundCurrently, 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).MethodsA 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.ResultsFGFR3 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.ConclusionsDifferential 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.

引用

页数：16

共 28 条

[1] First-line pembrolizumab in cisplatin-ineligible patients with locally advanced and unresectable or metastatic urothelial cancer (KEYNOTE-052): a multicentre, single-arm, phase 2 study [J].

Balar, Arjun V. ;

Castellano, Daniel ;

O'Donnell, Peter H. ;

Grivas, Petros ;

Vuky, Jacqueline ;

Powles, Thomas ;

Plimack, Elizabeth R. ;

Hahn, Noah M. ;

de Wit, Ronald ;

Pang, Lei ;

Savage, Mary J. ;

Perini, Rodolfo F. ;

Keefe, Stephen M. ;

Bajorin, Dean ;

Bellmunt, Joaquim .

LANCET ONCOLOGY, 2017, 18 (11) :1483-1492

[2] Pembrolizumab as Second-Line Therapy for Advanced Urothelial Carcinoma [J].

Bellmunt, J. ;

de Wit, R. ;

Vaughn, D. J. ;

Fradet, Y. ;

Lee, J. -L. ;

Fong, L. ;

Vogelzang, N. J. ;

Climent, M. A. ;

Petrylak, D. P. ;

Choueiri, T. K. ;

Necchi, A. ;

Gerritsen, W. ;

Gurney, H. ;

Quinn, D. I. ;

Culine, S. ;

Sternberg, C. N. ;

Mai, Y. ;

Poehlein, C. H. ;

Perini, R. F. ;

Bajorin, D. F. .

NEW ENGLAND JOURNAL OF MEDICINE, 2017, 376 (11) :1015-1026

[3]

Falchook GS, 2022, J CLIN ONCOL, V40

[4] Randomized phase III KEYNOTE-045 trial of pembrolizumab versus paclitaxel, docetaxel, or vinflunine in recurrent advanced urothelial cancer: results of >2 years of follow-up [J].

Fradet, Y. ;

Bellmunt, J. ;

Vaughn, D. J. ;

Lee, J. L. ;

Fong, L. ;

Vogelzang, N. J. ;

Climent, M. A. ;

Petrylak, D. P. ;

Choueiri, T. K. ;

Necchi, A. ;

Gerritsen, W. ;

Gurney, H. ;

Quinn, D., I ;

Culine, S. ;

Sternberg, C. N. ;

Nam, K. ;

Frenkl, T. L. ;

Perini, R. F. ;

de Wit, R. ;

Bajorin, D. F. .

ANNALS OF ONCOLOGY, 2019, 30 (06) :970-976

[5] A Consensus Molecular Classification of Muscle-invasive Bladder Cancer [J].

Kamoun, Aurelie ;

de Reynies, Aurelien ;

Allory, Yves ;

Sjodahl, Gottfrid ;

Robertson, A. Gordon ;

Seiler, Roland ;

Hoadley, Katherine A. ;

Groeneveld, Clarice S. ;

Al-Ahmadie, Hikmat ;

Choi, Woonyoung ;

Castro, Mauro A. A. ;

Fontugne, Jacqueline ;

Eriksson, Pontus ;

Mo, Qianxing ;

Kardos, Jordan ;

Zlotta, Alexandre ;

Hartmann, Arndt ;

Dinney, Colin P. ;

Bellmunt, Joaquim ;

Powles, Thomas ;

Malats, Nuria ;

Chan, Keith S. ;

Kim, William Y. ;

McConkey, David J. ;

Black, Peter C. ;

Dyrskjot, Lars ;

Hoglund, Mattias ;

Lerner, Seth P. ;

Real, Francisco X. ;

Radvanyi, Francois .

EUROPEAN UROLOGY, 2020, 77 (04) :420-433

[6] The mutational constraint spectrum quantified from variation in 141,456 humans [J].

Karczewski, Konrad J. ;

Francioli, Laurent C. ;

Tiao, Grace ;

Cummings, Beryl B. ;

Alfoldi, Jessica ;

Wang, Qingbo ;

Collins, Ryan L. ;

Laricchia, Kristen M. ;

Ganna, Andrea ;

Birnbaum, Daniel P. ;

Gauthier, Laura D. ;

Brand, Harrison ;

Solomonson, Matthew ;

Watts, Nicholas A. ;

Rhodes, Daniel ;

Singer-Berk, Moriel ;

England, Eleina M. ;

Seaby, Eleanor G. ;

Kosmicki, Jack A. ;

Walters, Raymond K. ;

Tashman, Katherine ;

Farjoun, Yossi ;

Banks, Eric ;

Poterba, Timothy ;

Wang, Arcturus ;

Seed, Cotton ;

Whiffin, Nicola ;

Chong, Jessica X. ;

Samocha, Kaitlin E. ;

Pierce-Hoffman, Emma ;

Zappala, Zachary ;

O'Donnell-Luria, Anne H. ;

Minikel, Eric Vallabh ;

Weisburd, Ben ;

Lek, Monkol ;

Ware, James S. ;

Vittal, Christopher ;

Armean, Irina M. ;

Bergelson, Louis ;

Cibulskis, Kristian ;

Connolly, Kristen M. ;

Covarrubias, Miguel ;

Donnelly, Stacey ;

Ferriera, Steven ;

Gabriel, Stacey ;

Gentry, Jeff ;

Gupta, Namrata ;

Jeandet, Thibault ;

Kaplan, Diane ;

Llanwarne, Christopher .

NATURE, 2020, 581 (7809) :434-+

[7] FGFR3 - a Central Player in Bladder Cancer Pathogenesis? [J].

Knowles, Margaret A. .

BLADDER CANCER, 2020, 6 (04) :403-423

[8] Trial watch: IDO inhibitors in cancer therapy [J].

Le Naour, Julie ;

Galluzzi, Lorenzo ;

Zitvogel, Laurence ;

Kroemer, Guido ;

Vacchelli, Erika .

ONCOIMMUNOLOGY, 2020, 9 (01)

[9] An integrated multi-omics analysis identifies prognostic molecular subtypes of non-muscle-invasive bladder cancer [J].

Lindskrog, Sia Viborg ;

Prip, Frederik ;

Lamy, Philippe ;

Taber, Ann ;

Groeneveld, Clarice S. ;

Birkenkamp-Demtroder, Karin ;

Jensen, Jorgen Bjerggaard ;

Strandgaard, Trine ;

Nordentoft, Iver ;

Christensen, Emil ;

Sokac, Mateo ;

Birkbak, Nicolai J. ;

Maretty, Lasse ;

Hermann, Gregers G. ;

Petersen, Astrid C. ;

Weyerer, Veronika ;

Grimm, Marc-Oliver ;

Horstmann, Marcus ;

Sjodahl, Gottfrid ;

Hoglund, Mattias ;

Steiniche, Torben ;

Mogensen, Karin ;

de Reynies, Aurelien ;

Nawroth, Roman ;

Jordan, Brian ;

Lin, Xiaoqi ;

Dragicevic, Dejan ;

Ward, Douglas G. ;

Goel, Anshita ;

Hurst, Carolyn D. ;

Raman, Jay D. ;

Warrick, Joshua, I ;

Segersten, Ulrika ;

Sikic, Danijel ;

van Kessel, Kim E. M. ;

Maurer, Tobias ;

Meeks, Joshua J. ;

DeGraff, David J. ;

Bryan, Richard T. ;

Knowles, Margaret A. ;

Simic, Tatjana ;

Hartmann, Arndt ;

Zwarthoff, Ellen C. ;

Malmstrom, Per-Uno ;

Malats, Nuria ;

Real, Francisco X. ;

Dyrskjot, Lars .

NATURE COMMUNICATIONS, 2021, 12 (01)

[10] Erdafitinib in Locally Advanced or Metastatic Urothelial Carcinoma [J].

Loriot, Y. ;

Necchi, A. ;

Park, S. H. ;

Garcia-Donas, J. ;

Huddart, R. ;

Burgess, E. ;

Fleming, M. ;

Rezazadeh, A. ;

Mellado, B. ;

Varlamov, S. ;

Joshi, M. ;

Duran, I. ;

Tagawa, S. T. ;

Zakharia, Y. ;

Zhong, B. ;

Stuyckens, K. ;

Santiago-Walker, A. ;

De Porre, P. ;

O'Hagan, A. ;

Avadhani, A. ;

Siefker-Radtke, A. O. .

NEW ENGLAND JOURNAL OF MEDICINE, 2019, 381 (04) :338-348

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