Cited by 173Cancer Immunotherapy and BiomarkersHepatocellular Carcinoma Treatment and PrognosisAngiogenesis and VEGF in Cancer

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Dual Vascular Endothelial Growth Factor Receptor and Fibroblast Growth Factor Receptor Inhibition Elicits Antitumor Immunity and Enhances Programmed Cell Death-1 Checkpoint Blockade in Hepatocellular Carcinoma

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Deng, Haijing, Kan, Anna, Lyu, Ning, Mu, Luwen, Han, Yi, Liu, Longzhong, Zhang, Yanyu, Duan, Youfa, Liao, Shuangye, Li, Shaolong, Xie, Qiankun, Gao, Tianxiao, Li, Yanrong, Zhang, Zhenfeng, Zhao, Ming·2020·Liver Cancer

DOI 10.1159/000505695PMC PMC7325120

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Abstract

Background and Aims: Combining anti-angiogenic therapy with immune checkpoint blockade with anti-programmed cell death-1 (PD-1) antibodies is a promising treatment for hepatocellular carcinoma (HCC). Tyrosine kinase inhibitors are well-known anti-angiogenic agents and offer potential for combination with anti-PD-1 antibodies. This study investigated the possible underlying immunomodulatory mechanisms of combined therapy. Methods: HCC tissue samples for RNA-sequencing (RNA-seq) were obtained from patients with differential prognoses following anti-PD-1 treatment. Recombinant basic fibroblast growth factor (bFGF) and vascular endothelial growth factor A (VEGFA) were used to stimulate T cells following lenvatinib or sorafenib treatment, respectively. T cell function was analyzed by flow cytometry and lactate dehydrogenase assay. In vivo experiments were conducted in murine H22 and Hepa 1–6 competent models of HCC. Local immune infiltration in the tumor microenvironment (TME) was assessed using multicolor flow cytometry. Gene regulation was evaluated by RNA-seq. Microvascular density was measured by immunohistochemistry, and PD-1 ligand (PD-L1) induction was quantified by western blot. Results: The baseline expression of VEGF and fibroblast growth factor (FGF) in patients with progressive disease was significantly higher than in patients achieving stable disease following anti-PD-1 treatment. VEGFA and bFGF significantly upregulated the expression of PD-1, cytotoxic T-lymphocyte-associated protein-4, and Tim-3 on T cells, while inhibiting the secretion of interferon gamma (IFNG) and granzyme B and suppressing T cell cytotoxicity. This immunosuppressive effect was reverted by lenvatinib but not sorafenib. Furthermore, dual lenvatinib/anti-PD-1 antibody therapy led to better antitumor effects than either sorafenib or fibroblast growth factor receptor (FGFR) inhibitor (BGJ398) in H22 murine models of HCC. Combined lenvatinib/anti-PD-1 treatment also led to long-term immune memory formation, while synergistically modulating the TME and enhancing the cytotoxic effect of T cells. Finally, lenvatinib inhibited PD-L1 expression on human umbilical vein endothelial cells, which improved the function of T cells. Conclusions: Inhibition of vascular endothelial growth factor receptor and FGFR augmented the efficacy of anti-PD-1 antibodies. Combined lenvatinib/anti-PD-1 treatment appears to exert antitumor activity by synergistically modulating effector T cell function in the TME and by mutually regulating tumor vessel normalization.

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Authors: Deng, H., Kan, A., Lyu, N., Mu, L., Han, Y., Liu, L., Zhang, Y., Duan, Y., Liao, S., Li, S., Xie, Q., Gao, T., Li, Y., Zhang, Z., & Zhao, M.
Affiliations: Sun Yat-sen University Cancer Center (CN)
Third Affiliated Hospital of Sun Yat-sen University (CN)
Second Affiliated Hospital of Guangzhou Medical University (CN)
ORCID: Deng, Haijing
Kan, Anna
Lyu, Ning
Mu, Luwen
Han, Yi
Liu, Longzhong
Zhang, Yanyu
Liao, Shuangye
Li, Shaolong
Xie, Qiankun
Li, Yanrong
Zhang, Zhenfeng
Zhao, Ming
Venue: Liver Cancer
Publisher: S. Karger AG
Published: 2020
Volume: 9
Issue: 3
Pages: 338-357
ISSN: 1664-5553 (ISSN-L)
2235-1795
DOI: 10.1159/000505695
PMC: PMC7325120
OpenAlex: W3008414152
Cited by: 173
References: 32
Citations by year: 2026: 15 · 2025: 23 · 2024: 44 · 2023: 32 · 2022: 33 · 2021: 24 · 2020: 2
FWCI: 8.22
Type: journal article
Language: en
Open access: gold
doi.org
Licence: cc-by-nc-nd
creativecommons.org/licenses/by-nc-nd/4.0/ (vor)
creativecommons.org/licenses/by-nc-nd/4.0/ (tdm)
Locations: Liver Cancer (publishedVersion, cc-by-nc-nd)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: Strong
National Natural Science Foundation of China (No. 81771956, 81771956)
Natural Science Foundation of Guangdong Province
Eisai
Topics: Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
Health Sciences › Medicine › Hepatology › Hepatocellular Carcinoma Treatment and Prognosis
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
Keywords: hepatocellular carcinoma, lenvatinib, sorafenib, anti-PD-1, VEGF-A, basic fibroblast growth factor, FGFR inhibition, BGJ398, PD-L1, tumor microenvironment, T cell cytotoxicity, immune checkpoint blockade, anti-angiogenic therapy, immunological memory, PD-1 ligands, tyrosine kinase inhibitors

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Dual Vascular Endothelial Growth Factor Receptor and Fibroblast Growth Factor Receptor Inhibition Elicits Antitumor Immunity and Enhances Programmed Cell Death-1 Checkpoint Blockade in Hepatocellular Carcinoma

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