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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
Open accessAbstract
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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“Besides, lenvatinib (VEGFR/FGFR inhibitor) plus α-PD-1 also showed a synergistic antitumor effect in the murine HCC model [235].”
From Combination strategies with PD-1/PD-L1 blockade: current advances and future directions (2022) · cites this paper as [235]
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“Recently, the combination regimens of PD-1/PD-L1 inhibitor and an antiangiogenic therapy have been proven to be an optimal treatment for advanced HCC [7, 8, 22, 23].”
BackgroundReal world evidence of Lenvatinib + anti PD-1 as an advanced line for metastatic melanoma
Stoff, R., Asher, N., Laks, S., Steinberg‐Silman, Y., Schachter, J., Shapira‐Frommer, R., Grynberg, S., & Ben‐Betzalel, G. (2023) · Frontiers in Oncology · doi:10.3389/fonc.2023.1180988 · Cited by 17
Kang, X., Wang, J., Kang, X., & Bai, L. (2023) · BMC Cancer · doi:10.1186/s12885-023-11166-w · Cited by 17
“But more importantly, lenvatinib can modulate the tumor microenvironment (TME) and enhance the cytotoxic effect of T cells [34].”
BackgroundDing, Y., Wang, S., Qiu, Z., Zhu, C., Wang, Y., Zhao, S., Qiu, W., Wang, K., Lv, J., & Qi, W. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1284937 · Cited by 15
Chen, S., Shuangyan, T., Shi, F., Cai, H., Wu, Z., Wang, L., Ma, P., Zhou, Y.-M., Mai, Q., Wang, F., et al. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1430571 · Cited by 17
Deep immune profiling of intrahepatic cholangiocarcinoma with CODEX multiplexed imaging
Baretti, M., Shekhar, S., Sahai, V., Shu, D. H., Howe, K., Gunchick, V., Assarzadegan, N., Kartalia, E., Zhu, Q., Hallab, E., et al. (2025) · Hepatology Communications · doi:10.1097/hc9.0000000000000632 · Cited by 17
“It is proposed that FGFR alterations may inhibit T-cell infiltration and expansion via the local inhibition of interferon-γ and GZMB, [38 – 40] although our results showed that CD4+ T cells in mFGFR2 tumors tended to have increased GZMB expression compared to other molecular subtypes.”
Pu, Q., Yu, L., Wang, X., Yan, H., Xie, Y., Jiang, Y., & Yang, Z. (2022) · Journal of Cancer · doi:10.7150/jca.74829 · Cited by 17
“According to the SMD values and 95% CIs, combination therapy significantly decreased VEGF levels (-2.07, -3.10 ~ -1.04) (Supplementary Material Document 3: Forest plot) and ST combined with CKSI (-2.28, -2.88 ~ -1.68), XZYGP (-4.16, -4.77 ~ -3.54), SQFZI (-1.48, -1.89 ~ -1.07), ADI (-0.85, -1.12 ~ -0.58) and Huaier (-…”
BackgroundInfluentialYuan, G., Li, R., Li, Q., Hu, X., Ruan, J., Fan, W., Wang, J., Huang, W. M., Zang, M., & Chen, J. (2021) · Annals of Translational Medicine · doi:10.21037/atm-21-3020 · Cited by 13
Zhang, T., Zhu, C., Zhang, N., Zhang, L., Wang, S., Xun, Z., Xu, Y., Yang, X., Lü, X., & Zhao, H. (2024) · International Immunopharmacology · doi:10.1016/j.intimp.2024.111642 · Cited by 13
Lin, Y.-S., Li, S., Yang, X., Guo, R., Huang, Y.-H., Bai, K., Weng, J., & Yun, J. (2024) · Journal of Cancer Research and Clinical Oncology · doi:10.1007/s00432-024-05795-2 · Cited by 13
“The inhibition of VEGFR and FGFR can enhance the effect of PD-1 checkpoint blockade in HCC therapy (Deng et al. 2020).”
BackgroundSelf-citationTriple-color fluorescence co-localization of PD-L1-overexpressing cancer exosomes
Wei, J., Zhu, K., Chen, Z., Yang, Z., Yang, K., Wang, Z., Zong, S., & Cui, Y. (2022) · Microchimica Acta · doi:10.1007/s00604-022-05278-6 · Cited by 13
Fu, S., Xu, Y., Ye, M., He, M., Chen, Z., Huang, S., Li, D., Lv, Y., & Wu, J. (2024) · Cancer Medicine · doi:10.1002/cam4.7105 · Cited by 12
“25–28 Additionally, oxaliplatin can induce immunogenic cell death also contributes to the enhanced response to immunotherapy.”
BackgroundXie, S., Zhong, J., Zhang, Z., Huang, W., Lin, X., Pan, Y., Kong, X., Xia, H., Yu, Z., Ni, H., et al. (2023) · Cancer Cell International · doi:10.1186/s12935-023-02975-x · Cited by 11
“As the cancer progression, tumor cells, vascular endothelial cells, immune cells and pericytes produce excessive proangiogenic factors, such as VEGF [27], bFGF [28], and HGF [29, 30], to break this balance and lead to excessive activation and recruitment of endothelial cells and pericytes.”
BackgroundSelf-citationLi, J., Li, Z., & Wang, K. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1550752 · Cited by 11
Wang, F., Chen, W., Jia, Y., He, T., Wu, S., Xiang, J., Chen, R., Jiang, Q., Yu, T., Lan, Y., et al. (2025) · Cancer Medicine · doi:10.1002/cam4.70994 · Cited by 13
“In this context, the expression of immune checkpoints such as PD-1, CTLA-4, TIM3, and LAG3 also significantly increases [37, 38].”
Self-citationLu, Y., Jin, J., Du, Q., Hu, M. S., Wei, Y., Wang, M., Li, H., & Li, Q. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.730240 · Cited by 12
Han, R., Gan, L., Lang, M., Ren, S., Liu, D., Li, G., Liu, Y., Tian, X., Zhu, K., Sun, L., et al. (2024) · World Journal of Gastroenterology · doi:10.3748/wjg.v30.i43.4620 · Cited by 9
“It also plays an immunomodulatory role by blocking FGFR4, reducing tumor PD-1 expression, and inhibiting Treg differentiation[36,37].”
Nikoo, M., Hassan, Z. F., Mardasi, M., Rostamnezhad, E., Roozbahani, F., Rahimi, S., & Mohammadi, J. (2023) · Pathology - Research and Practice · doi:10.1016/j.prp.2023.154473 · Cited by 9
Zhang, J.-X., Chen, Y.-X., Zhou, C., Liu, J., Liu, S., Shi, H., & Zu, Q. (2022) · Canadian Journal of Gastroenterology and Hepatology · doi:10.1155/2022/7982118 · Cited by 9
“1/anti-PD-L1 efficacy by reversing VEGF-mediated immunosuppression [22, 23].”
He, P., Wan, H., Wan, J., Jiang, H., Yu, Y., Xie, K., & Wu, H. (2022) · Frontiers in Oncology · doi:10.3389/fonc.2022.1015527 · Cited by 9
“Logically, patients with higher expression levels of PD-1/PD-L1 respond better to PD-L1 inhibitors, which has been reported in many types of cancers, such as lung cancers (97) and melanoma (98).”
BackgroundInfluentialYu, W., Liu, W., Zhang, K., Chen, S., & Wang, X. (2023) · Cancer Immunology Immunotherapy · doi:10.1007/s00262-023-03511-6 · Cited by 9
“Some studies have confirmed that tyrosine kinase inhibitors synergize with anti-PD-1 antibodies and augment the efficacy of immunotherapy [24, 25].”
BackgroundCai, H., Chen, S., Wu, Z., Wang, F., Tang, S., Chen, L., & Guo, W. (2024) · Journal of Hepatocellular Carcinoma · doi:10.2147/jhc.s439001 · Cited by 8
Rajak, D., Nema, P., Sahu, A., Vishwakarma, S., & Kashaw, S. K. (2025) · Computers in Biology and Medicine · doi:10.1016/j.compbiomed.2025.111120 · Cited by 9
Ci, H., Wang, X., Shen, K., Du, W., Zhou, J., Fu, Y., Dong, Q., & Jia, H. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24043324 · Cited by 8
Breitenecker, K., Hedrich, V., Pupp, F., Chen, D., Řezníčková, E., Ortmayr, G., Huber, H., Weber, G., Balcar, L., Pinter, M., et al. (2023) · Frontiers in Oncology · doi:10.3389/fonc.2023.1238883 · Cited by 8
“FGFR1 transcript levels are elevated in HCC patients at advanced stages and bFGF is able to induce PD-1 expression on T cells, therefore limiting their functionality (47).”
BackgroundDiagnostic, prognostic, and therapeutic potential of exosomal microRNAs in renal cancer
Yu, X., Du, Z., Zhu, P., & Liao, B. (2024) · Pharmacological Reports · doi:10.1007/s43440-024-00568-7 · Cited by 11
“Consistently, the other study indicated that high expression of VEGFA could inhibit the maturation of CD8 + T cells, thus inducing immune escape of hepatoma cells [83].”
Jin, X., Zhang, K., Fang, T., Zeng, X., Xu, Y., Tang, J., Liang, Z., Xie, L., & Zhao, D. F. (2022) · Frontiers in Oncology · doi:10.3389/fonc.2022.951303 · Cited by 8
Signaling molecules in the microenvironment of hepatocellular carcinoma
Chen, W., Tan, M., Zhang, H., Gao, T., Ren, J., Cheng, S., & Chen, J. (2024) · Functional & Integrative Genomics · doi:10.1007/s10142-024-01427-7 · Cited by 7
“…intracellular signaling pathways in the cells while also mediating the recruitment and activation of immune cells by acting on receptors on the surface of the cells, thus indirectly participating in tumor migration and invasion (Wang et al. 2023; Deng et al. 2020; You et al. 2017; Li et al. 2019a).”
Self-citationLyrarakis, G., Liontos, M., Anastasopoulou, A. N., Bouros, S., Gkoufa, A., Diamantopoulos, P. T., Gogas, H. J., & Ziogas, D. C. (2024) · Frontiers in Oncology · doi:10.3389/fonc.2024.1420879 · Cited by 7
Fujiwara, Y., Kuroda, H., Abe, T., Kakisaka, K., Nakaya, I., Ito, A., Watanabe, T., Yusa, K., Nagasawa, T., Sato, H., et al. (2024) · Drugs - Real World Outcomes · doi:10.1007/s40801-024-00458-7 · Cited by 6
“In addition, there have been clinical evidence indicating MTAs to induce the expression of PD-L1 in tumors [27, 28].”
Therapies targeting triple-negative breast cancer: a perspective on anti-FGFR
Chen, J., Wang, Q., Wu, H.-Y., Huang, X., & Cao, C. (2025) · Frontiers in Oncology · doi:10.3389/fonc.2024.1415820 · Cited by 6
Oncogenic Signalling Pathways in Cancer Immunotherapy: Leader or Follower in This Delicate Dance?
Cartwright, D., Kidd, A. C., Ansel, S., Ascierto, M. L., & Spiliopoulou, P. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26094393 · Cited by 9
“However, the preclinical literature supports the use of both selective and multi-target TKI FGFRi-ICI combination therapy, with a particular emphasis on the enhancement of the immune-depleted TME in FGFR-mutated cancers [105,115,121].”
Targeting USP47 enhances immunotherapy in hepatocellular carcinoma by destabilizing PD-L1
Jiang, Y., Yu, Z., Wang, J., Wu, Y., Li, Z., Le, T., Yang, C., Wei, Y., Zhang, G., & Ma, H. (2025) · International Immunopharmacology · doi:10.1016/j.intimp.2025.115024 · Cited by 7
Metadata
- 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
- Venue
- Liver Cancer
- Publisher
- S. Karger AG
- Published
- 2020
- Volume
- 9
- Issue
- 3
- Pages
- 338-357
- ISSN
- 1664-5553 (ISSN-L)
- 2235-1795
- 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
- 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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