Lenvatinib Induces Immunogenic Cell Death and Triggers Toll-Like Receptor-3/4 Ligands in Hepatocellular Carcinoma

References

• Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68:394–424. doi:10.3322/caac.21492
   PubMed Web of Science ®Google Scholar
• Kuczynski EA, Lee CR, Man S, Chen E, Kerbel RS. Effects of Sorafenib Dose on Acquired Reversible Resistance and Toxicity in Hepatocellular Carcinoma. Cancer Res. 2015;75:2510–2519. doi:10.1158/0008-5472.CAN-14-3687
   PubMed Web of Science ®Google Scholar
• Finn RS, Ikeda M, Zhu AX, et al. Phase Ib Study of Lenvatinib Plus Pembrolizumab in Patients With Unresectable Hepatocellular Carcinoma. J Clin Oncol. 2020;38:2960–2970. doi:10.1200/JCO.20.00808
   PubMed Web of Science ®Google Scholar
• Qin S, Bi F, Gu S, et al. Donafenib Versus Sorafenib in First-Line Treatment of Unresectable or Metastatic Hepatocellular Carcinoma: a Randomized, Open-Label, Parallel-Controlled Phase II-III Trial. J Clin Oncol. 2021;39:3002–3011. doi:10.1200/JCO.21.00163
   PubMed Web of Science ®Google Scholar
• Qin S, Ren Z, Feng YH, et al. Atezolizumab plus Bevacizumab versus Sorafenib in the Chinese Subpopulation with Unresectable Hepatocellular Carcinoma: Phase 3 Randomized, Open-Label IMbrave150 Study. Liver Cancer. 2021;10:296–308. doi:10.1159/000513486
   PubMed Web of Science ®Google Scholar
• Hiraoka A, Kumada T, Fukunishi S, et al. Post-Progression Treatment Eligibility of Unresectable Hepatocellular Carcinoma Patients Treated with Lenvatinib. Liver Cancer. 2020;9:73–83. doi:10.1159/000503031
   PubMed Web of Science ®Google Scholar
• Kimura T, Kato Y, Ozawa Y, et al. Immunomodulatory activity of lenvatinib contributes to antitumor activity in the Hepa1-6 hepatocellular carcinoma model. Cancer Sci. 2018;109:3993–4002. doi:10.1111/cas.13806
   PubMed Web of Science ®Google Scholar
• Deng H, Kan A, Lyu N, et al. 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. Liver Cancer. 2020;9:338–357. doi:10.1159/000505695
   PubMed Web of Science ®Google Scholar
• Torrens L, Montironi C, Puigvehí M, et al. Immunomodulatory Effects of Lenvatinib Plus Anti-Programmed Cell Death Protein 1 in Mice and Rationale for Patient Enrichment in Hepatocellular Carcinoma. Hepatology. 2021;74:2652–2669. doi:10.1002/hep.32023
   PubMed Web of Science ®Google Scholar
• Zhang Q, Liu H, Wang H, et al. Lenvatinib promotes antitumor immunity by enhancing the tumor infiltration and activation of NK cells. Am J Cancer Res. 2019;9:1382–1395.
   PubMed Web of Science ®Google Scholar
• Galluzzi L, Buqué A, Kepp O, Zitvogel L, Kroemer G. Immunogenic cell death in cancer and infectious disease. Nat Rev Immunol. 2017;17:97–111. doi:10.1038/nri.2016.107
   PubMed Web of Science ®Google Scholar
• Kroemer G, Galassi C, Zitvogel L, Galluzzi L. Immunogenic cell stress and death. Nat Immunol. 2022;23:487–500. doi:10.1038/s41590-022-01132-2
   PubMed Web of Science ®Google Scholar
• Sistigu A, Yamazaki T, Vacchelli E, et al. Cancer cell-autonomous contribution of type I interferon signaling to the efficacy of chemotherapy. Nat Med. 2014;20:1301–1309. doi:10.1038/nm.3708
   PubMed Web of Science ®Google Scholar
• Garg AD, Agostinis P. Cell death and immunity in cancer: from danger signals to mimicry of pathogen defense responses. Immunol Rev. 2017;280:126–148. doi:10.1111/imr.12574
   PubMed Web of Science ®Google Scholar
• Leuchte K, Staib E, Thelen M, et al. Microwave ablation enhances tumor-specific immune response in patients with hepatocellular carcinoma. Cancer Immunol Immunother. 2021;70:893–907. doi:10.1007/s00262-020-02734-1
   PubMed Web of Science ®Google Scholar
• Friedman D, Baird JR, Young KH, et al. Programmed cell death-1 blockade enhances response to stereotactic radiation in an orthotopic murine model of hepatocellular carcinoma. Hepatol Res. 2017;47:702–714. doi:10.1111/hepr.12789
   PubMed Web of Science ®Google Scholar
• Pinato DJ, Murray SM, Forner A, et al. Trans-arterial chemoembolization as a loco-regional inducer of immunogenic cell death in hepatocellular carcinoma: implications for immunotherapy. J Immunother Cancer. 2021;9.
   Google Scholar
• Casares N, Pequignot MO, Tesniere A, et al. Caspase-dependent immunogenicity of doxorubicin-induced tumor cell death. J Exp Med. 2005;202:1691–1701. doi:10.1084/jem.20050915
   PubMed Web of Science ®Google Scholar
• Zechendorf E, O’Riordan CE, Stiehler L, et al. Ribonuclease 1 attenuates septic cardiomyopathy and cardiac apoptosis in a murine model of polymicrobial sepsis. JCI Insight. 2020;5:e131571. doi:10.1172/jci.insight.131571
   PubMed Web of Science ®Google Scholar
• Cui J, Song Y, Li Y, et al. USP3 inhibits type I interferon signaling by deubiquitinating RIG-I-like receptors. Cell Res. 2014;24:400–416. doi:10.1038/cr.2013.170
   PubMed Web of Science ®Google Scholar
• Wagener BM, Hu PJ, Oh J-Y, et al. Role of heme in lung bacterial infection after trauma hemorrhage and stored red blood cell transfusion: a preclinical experimental study. PLoS Med. 2018;15:e1002522. doi:10.1371/journal.pmed.1002522
   PubMed Web of Science ®Google Scholar
• Ikeda M, Okusaka T, Mitsunaga S, et al. Safety and Pharmacokinetics of Lenvatinib in Patients with Advanced Hepatocellular Carcinoma. Clin Cancer Res. 2016;22(6):1385–1394. doi:10.1158/1078-0432.CCR-15-1354
   PubMed Web of Science ®Google Scholar
• Hoshi T, Watanabe Miyano S, Watanabe H, et al. Lenvatinib induces death of human hepatocellular carcinoma cells harboring an activated FGF signaling pathway through inhibition of FGFR-MAPK cascades. Biochem Biophys Res Commun. 2019;513:1–7. doi:10.1016/j.bbrc.2019.02.015
   PubMed Web of Science ®Google Scholar
• Du Four S, Maenhout SK, Niclou SP, Thielemans K, Neyns B, Aerts JL. Combined VEGFR and CTLA-4 blockade increases the antigen-presenting function of intratumoral DCs and reduces the suppressive capacity of intratumoral MDSCs. Am J Cancer Res. 2016;6:2514–2531.
   PubMed Web of Science ®Google Scholar
• Passirani C, Vessières A, La Regina G, Link W, Silvestri R. Modulating undruggable targets to overcome cancer therapy resistance. Drug Resist Updat. 2022;60:100788. doi:10.1016/j.drup.2021.100788
   PubMed Web of Science ®Google Scholar
• Liu X, Xie X, Ren Y, et al. The role of necroptosis in disease and treatment. MedComm. 2021;2:730–755. doi:10.1002/mco2.108
   PubMedGoogle Scholar
• Yi C, Chen L, Lin Z, et al. Lenvatinib Targets FGF Receptor 4 to Enhance Antitumor Immune Response of Anti-Programmed Cell Death-1 in HCC. Hepatology. 2021;74:2544–2560. doi:10.1002/hep.31921
   PubMed Web of Science ®Google Scholar
• Adachi Y, Kamiyama H, Ichikawa K, et al. Inhibition of FGFR Reactivates IFNγ Signaling in Tumor Cells to Enhance the Combined Antitumor Activity of Lenvatinib with Anti-PD-1 Antibodies. Cancer Res. 2022;82:292–306. doi:10.1158/0008-5472.CAN-20-2426
   PubMed Web of Science ®Google Scholar
• Lu LG, Zhou ZL, Wang XY, et al. PD-L1 blockade liberates intrinsic antitumourigenic properties of glycolytic macrophages in hepatocellular carcinoma. Gut. 2022;71(12):2551–2560. doi:10.1136/gutjnl-2021-326350
   PubMed Web of Science ®Google Scholar
• Wu Q, Zhou W, Yin S, et al. Blocking Triggering Receptor Expressed on Myeloid Cells-1-Positive Tumor-Associated Macrophages Induced by Hypoxia Reverses Immunosuppression and Anti-Programmed Cell Death Ligand 1 Resistance in Liver Cancer. Hepatology. 2019;70(1):198–214. doi:10.1002/hep.30593
   PubMed Web of Science ®Google Scholar
• Fu Y, Mackowiak B, Feng D, et al. MicroRNA-223 attenuates hepatocarcinogenesis by blocking hypoxia-driven angiogenesis and immunosuppression. Gut. 2023. doi:10.1136/gutjnl-2022-327924
   Web of Science ®Google Scholar
• Li D, Hu M, Liu Y, et al. CD24-p53 axis suppresses diethylnitrosamine-induced hepatocellular carcinogenesis by sustaining intrahepatic macrophages. Cell Discov. 2018;4:6. doi:10.1038/s41421-017-0007-9
   PubMed Web of Science ®Google Scholar
• Das S, Shapiro B, Vucic EA, Vogt S, Bar-Sagi D. Tumor Cell-Derived IL1β Promotes Desmoplasia and Immune Suppression in Pancreatic Cancer. Cancer Res. 2020;80:1088–1101. doi:10.1158/0008-5472.CAN-19-2080
   PubMed Web of Science ®Google Scholar
• Klein JC, Wild CA, Lang S, Brandau S. Differential immunomodulatory activity of tumor cell death induced by cancer therapeutic toll-like receptor ligands. Cancer Immunol Immunother. 2016;65:689–700. doi:10.1007/s00262-016-1828-3
   PubMed Web of Science ®Google Scholar
• Chew V, Tow C, Huang C, et al. Toll-like receptor 3 expressing tumor parenchyma and infiltrating natural killer cells in hepatocellular carcinoma patients. J Natl Cancer Inst. 2012;104:1796–1807. doi:10.1093/jnci/djs436
   PubMedGoogle Scholar
• Bonnin M, Fares N, Testoni B, et al. Toll-like receptor 3 downregulation is an escape mechanism from apoptosis during hepatocarcinogenesis. J Hepatol. 2019;71:763–772. doi:10.1016/j.jhep.2019.05.031
   PubMed Web of Science ®Google Scholar
• Zheng Q, Martin RC, Shi X, et al. Lack of FGF21 promotes NASH-HCC transition via hepatocyte-TLR4-IL-17A signaling. Theranostics. 2020;10:9923–9936. doi:10.7150/thno.45988
   PubMed Web of Science ®Google Scholar
• Dapito DH, Mencin A, Gwak GY, et al. Promotion of hepatocellular carcinoma by the intestinal microbiota and TLR4. Cancer Cell. 2012;21:504–516. doi:10.1016/j.ccr.2012.02.007
   PubMed Web of Science ®Google Scholar
• Wen ZF, Liu H, Gao R, et al. Tumor cell-released autophagosomes (TRAPs) promote immunosuppression through induction of M2-like macrophages with increased expression of PD-L1. J Immunother Cancer. 2018;6:151. doi:10.1186/s40425-018-0452-5
   PubMed Web of Science ®Google Scholar
• Fleming V, Hu X, Weller C, et al. Melanoma Extracellular Vesicles Generate Immunosuppressive Myeloid Cells by Upregulating PD-L1 via TLR4 Signaling. Cancer Res. 2019;79:4715–4728. doi:10.1158/0008-5472.CAN-19-0053
   PubMed Web of Science ®Google Scholar
• Jang GY, Kim YS, Lee SE, et al. Improvement of DC-based vaccines using adjuvant TLR4-binding 60S acidic ribosomal protein P2 and immune checkpoint inhibitors. Cancer Immunol Immunother. 2021;70:1075–1088. doi:10.1007/s00262-020-02759-6
   PubMed Web of Science ®Google Scholar
• Farias A, Soto A, Puttur F, et al. A TLR4 agonist improves immune checkpoint blockade treatment by increasing the ratio of effector to regulatory cells within the tumor microenvironment. Sci Rep. 2021;11:15406. doi:10.1038/s41598-021-94837-7
   PubMed Web of Science ®Google Scholar
• Seya T, Takeda Y, Matsumoto M. A Toll-like receptor 3 (TLR3) agonist ARNAX for therapeutic immunotherapy. Adv Drug Deliv Rev. 2019;147:37–43. doi:10.1016/j.addr.2019.07.008
   PubMed Web of Science ®Google Scholar
• Takeda Y, Kataoka K, Yamagishi J, Ogawa S, Seya T, Matsumoto M. A TLR3-Specific Adjuvant Relieves Innate Resistance to PD-L1 Blockade without Cytokine Toxicity in Tumor Vaccine Immunotherapy. Cell Rep. 2017;19:1874–1887. doi:10.1016/j.celrep.2017.05.015
   PubMed Web of Science ®Google Scholar