Fibroblast growth factor inhibition by molecular-targeted agents mitigates immunosuppressive tissue microenvironment in hepatocellular carcinoma
© 2023. The Author(s)..
BACKGROUND & AIMS: Combination immunotherapy refers to the use of immune checkpoint inhibitors (ICI) and molecular-targeted agents (MTA), which have recently been approved for the treatment of advanced hepatocellular carcinoma (HCC). Owing to its relatively low antitumor effect (up to 30%), sequential therapy following ICIs treatment is required in patients with HCC. This study aimed to determine the impact of MTAs on the tumor immune microenvironment (TIME).
METHODS: We established immune syngeneic orthotopic HCC mouse models using Hep-55.1C and Hep-53.4, and treated them with MTAs (lenvatinib, sorafenib, regorafenib, cabozantinib, and DC101 as anti-vascular endothelial growth factor receptor-2 antibodies, and AZD4547 as a fibroblast growth factor receptor (FGFR)-1/2/3/4 inhibitor) for 2 weeks. Subsequently, alterations in the TIME caused by MTAs were evaluated using immunohistochemistry (antibodies for CD3, CD8, Foxp3, Granzyme B, Arginase-1, NK1.1, F4/80, CD11c, PD-1, and PD-L1). We conducted RNA-seq analysis using lenvatinib- and AZD4547-treated tumors. To confirm the clinical relevance of these findings, we analyzed the transcriptome data of human HCC cells (MHCC-97H) treated with various concentrations of lenvatinib for 24 h using RNA-seq data from the Gene Expression Omnibus database.
RESULTS: The number of Foxp3- and F4/80-positive cells in the TIME was decreased in many MTAs. Cabozantinib increased the numbers in NK1.1-, Granzyme B, and CD11c-positive cells. Lenvatinib and AZD4547 increased the number of CD8, Granzyme B, and PD-L1-positive cells. Gene ontology enrichment analysis revealed that lipid metabolism-related genes were downregulated by lenvatinib and AZD4547. In total, 161 genes downregulated by FGFR inhibition in rodent models overlapped with those downregulated by lenvatinib in human HCC cells.
CONCLUSIONS: In this study, we showed that cabozantinib activated the innate immune system, and lenvatinib and AZD4547, which commonly inhibit FGFR signaling, altered TIME to a hot immune state by downregulating lipid metabolism-related genes. These findings support the therapeutic use of combination immunotherapies.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2024 |
|---|---|
| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:18 |
|---|---|
| Enthalten in: |
Hepatology international - 18(2024), 2 vom: 21. Apr., Seite 610-622 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Suzuki, Hiroyuki [VerfasserIn] |
|---|
| Links: |
|---|
| Anmerkungen: |
Date Completed 15.04.2024 Date Revised 26.04.2024 published: Print-Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1007/s12072-023-10603-z |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM363570500 |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM363570500 | ||
| 003 | DE-627 | ||
| 005 | 20240426233330.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231226s2024 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1007/s12072-023-10603-z |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1388.xml |
| 035 | |a (DE-627)NLM363570500 | ||
| 035 | |a (NLM)37864726 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Suzuki, Hiroyuki |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Fibroblast growth factor inhibition by molecular-targeted agents mitigates immunosuppressive tissue microenvironment in hepatocellular carcinoma |
| 264 | 1 | |c 2024 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 15.04.2024 | ||
| 500 | |a Date Revised 26.04.2024 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2023. The Author(s). | ||
| 520 | |a BACKGROUND & AIMS: Combination immunotherapy refers to the use of immune checkpoint inhibitors (ICI) and molecular-targeted agents (MTA), which have recently been approved for the treatment of advanced hepatocellular carcinoma (HCC). Owing to its relatively low antitumor effect (up to 30%), sequential therapy following ICIs treatment is required in patients with HCC. This study aimed to determine the impact of MTAs on the tumor immune microenvironment (TIME) | ||
| 520 | |a METHODS: We established immune syngeneic orthotopic HCC mouse models using Hep-55.1C and Hep-53.4, and treated them with MTAs (lenvatinib, sorafenib, regorafenib, cabozantinib, and DC101 as anti-vascular endothelial growth factor receptor-2 antibodies, and AZD4547 as a fibroblast growth factor receptor (FGFR)-1/2/3/4 inhibitor) for 2 weeks. Subsequently, alterations in the TIME caused by MTAs were evaluated using immunohistochemistry (antibodies for CD3, CD8, Foxp3, Granzyme B, Arginase-1, NK1.1, F4/80, CD11c, PD-1, and PD-L1). We conducted RNA-seq analysis using lenvatinib- and AZD4547-treated tumors. To confirm the clinical relevance of these findings, we analyzed the transcriptome data of human HCC cells (MHCC-97H) treated with various concentrations of lenvatinib for 24 h using RNA-seq data from the Gene Expression Omnibus database | ||
| 520 | |a RESULTS: The number of Foxp3- and F4/80-positive cells in the TIME was decreased in many MTAs. Cabozantinib increased the numbers in NK1.1-, Granzyme B, and CD11c-positive cells. Lenvatinib and AZD4547 increased the number of CD8, Granzyme B, and PD-L1-positive cells. Gene ontology enrichment analysis revealed that lipid metabolism-related genes were downregulated by lenvatinib and AZD4547. In total, 161 genes downregulated by FGFR inhibition in rodent models overlapped with those downregulated by lenvatinib in human HCC cells | ||
| 520 | |a CONCLUSIONS: In this study, we showed that cabozantinib activated the innate immune system, and lenvatinib and AZD4547, which commonly inhibit FGFR signaling, altered TIME to a hot immune state by downregulating lipid metabolism-related genes. These findings support the therapeutic use of combination immunotherapies | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a APOC1 | |
| 650 | 4 | |a VIPR1 | |
| 650 | 4 | |a Fibroblast growth factor | |
| 650 | 4 | |a Hepatocellular carcinoma | |
| 650 | 4 | |a Immune checkpoint inhibitor | |
| 650 | 4 | |a Molecular targeting | |
| 650 | 4 | |a Orthotopic | |
| 650 | 4 | |a RNA sequencing | |
| 650 | 4 | |a Tumor immune microenvironment | |
| 650 | 4 | |a Vascular endothelial growth factor receptor | |
| 650 | 7 | |a lenvatinib |2 NLM | |
| 650 | 7 | |a EE083865G2 |2 NLM | |
| 650 | 7 | |a cabozantinib |2 NLM | |
| 650 | 7 | |a 1C39JW444G |2 NLM | |
| 650 | 7 | |a AZD4547 |2 NLM | |
| 650 | 7 | |a B7-H1 Antigen |2 NLM | |
| 650 | 7 | |a Granzymes |2 NLM | |
| 650 | 7 | |a EC 3.4.21.- |2 NLM | |
| 650 | 7 | |a Fibroblast Growth Factors |2 NLM | |
| 650 | 7 | |a 62031-54-3 |2 NLM | |
| 650 | 7 | |a Antineoplastic Agents |2 NLM | |
| 650 | 7 | |a Immunosuppressive Agents |2 NLM | |
| 650 | 7 | |a Protein Kinase Inhibitors |2 NLM | |
| 650 | 7 | |a Forkhead Transcription Factors |2 NLM | |
| 650 | 7 | |a Quinolines |2 NLM | |
| 650 | 7 | |a Pyrazoles |2 NLM | |
| 650 | 7 | |a Benzamides |2 NLM | |
| 650 | 7 | |a Phenylurea Compounds |2 NLM | |
| 650 | 7 | |a Anilides |2 NLM | |
| 650 | 7 | |a Piperazines |2 NLM | |
| 650 | 7 | |a Pyridines |2 NLM | |
| 700 | 1 | |a Iwamoto, Hideki |e verfasserin |4 aut | |
| 700 | 1 | |a Tanaka, Toshimitsu |e verfasserin |4 aut | |
| 700 | 1 | |a Sakaue, Takahiko |e verfasserin |4 aut | |
| 700 | 1 | |a Imamura, Yasuko |e verfasserin |4 aut | |
| 700 | 1 | |a Masuda, Atsutaka |e verfasserin |4 aut | |
| 700 | 1 | |a Nakamura, Toru |e verfasserin |4 aut | |
| 700 | 1 | |a Koga, Hironori |e verfasserin |4 aut | |
| 700 | 1 | |a Hoshida, Yujin |e verfasserin |4 aut | |
| 700 | 1 | |a Kawaguchi, Takumi |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Hepatology international |d 2007 |g 18(2024), 2 vom: 21. Apr., Seite 610-622 |w (DE-627)NLM190585528 |x 1936-0541 |7 nnns |
| 773 | 1 | 8 | |g volume:18 |g year:2024 |g number:2 |g day:21 |g month:04 |g pages:610-622 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1007/s12072-023-10603-z |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 18 |j 2024 |e 2 |b 21 |c 04 |h 610-622 | ||