Sorafenib Induces Pyroptosis in Macrophages and Triggers Natural Killer Cell-Mediated Cytotoxicity Against Hepatocellular Carcinoma.
Analysis of Variance
Animals
Carcinoma, Hepatocellular
/ drug therapy
Cytokines
/ metabolism
Disease Models, Animal
Female
Flow Cytometry
Humans
Injections, Intravenous
Killer Cells, Natural
/ metabolism
Liver Neoplasms
/ drug therapy
Macrophages
Mice
Mice, Transgenic
Protein Kinase Inhibitors
/ pharmacology
Pyroptosis
/ drug effects
Random Allocation
Sorafenib
/ pharmacology
Tumor Burden
/ drug effects
Tumor Cells, Cultured
X-Ray Microtomography
/ methods
Xenograft Model Antitumor Assays
Journal
Hepatology (Baltimore, Md.)
ISSN: 1527-3350
Titre abrégé: Hepatology
Pays: United States
ID NLM: 8302946
Informations de publication
Date de publication:
10 2019
10 2019
Historique:
received:
29
11
2018
accepted:
12
04
2019
pubmed:
20
4
2019
medline:
26
6
2020
entrez:
20
4
2019
Statut:
ppublish
Résumé
Antiangiogenic and cytotoxic effects are considered the principal mechanisms of action of sorafenib, a multitarget kinase inhibitor approved for the treatment of hepatocellular carcinoma (HCC). We report that sorafenib also acts through direct immune modulation, indispensable for its antitumor activity. In vivo cell depletion experiments in two orthotopic HCC mouse models as well as in vitro analysis identified macrophages (MΦ) as the key mediators of the antitumoral effect and demonstrate a strong interdependency of MΦ and natural killer (NK) cells for efficient tumor cell killing. Caspase 1 analysis in sorafenib-treated MΦ revealed an induction of pyroptosis. As a result, cytotoxic NK cells become activated when cocultured with sorafenib-treated MΦ, leading to tumor cell death. In addition, sorafenib was found to down-regulate major histocompatibility complex class I expression of tumor cells, which may reduce the tumor responsiveness to immune checkpoint therapies and favor NK-cell response. In vivo cytokine blocking revealed that sorafenib efficacy is abrogated after inhibition of interleukins 1B and 18. Conclusion: We report an immunomodulatory mechanism of sorafenib involving MΦ pyroptosis and unleashing of an NK-cell response that sets it apart from other spectrum kinase inhibitors as a promising immunotherapy combination partner for the treatment of HCC.
Substances chimiques
Cytokines
0
Protein Kinase Inhibitors
0
Sorafenib
9ZOQ3TZI87
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1280-1297Subventions
Organisme : Roche Diagnostics GmbH
Pays : International
Informations de copyright
© 2019 by the American Association for the Study of Liver Diseases.
Références
Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer 2015;136:359-386.
Janevska D, Chaloska-Ivanova V, Janevski V. Hepatocellular carcinoma: risk factors, diagnosis and treatment. Open Access Maced J Med Sci 2015;3:732-736.
Keating GM. Sorafenib: a review in hepatocellular carcinoma. Target Oncol 2017;12:243-253.
Wilhelm SM, Adnane L, Newell P, Villanueva A, Llovet JM, Lynch M. Preclinical overview of sorafenib, a multikinase inhibitor that targets both Raf and VEGF and PDGF receptor tyrosine kinase signaling. Mol Cancer Ther 2008;7:3129-3140.
Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 2008;359:378-390.
Mamdani H, Wu H, O'Neil BH, Sehdev A. Excellent response to anti-PD-1 therapy in a patient with hepatocellular carcinoma: case report and review of literature. Discov Med 2017;23:331-336.
Inarrairaegui M, Melero I, Sangro B. Immunotherapy of hepatocellular carcinoma: facts and hopes. Clin Cancer Res 2018;24:1518-1524.
Kudo M. Immune checkpoint inhibition in hepatocellular carcinoma: basics and ongoing clinical trials. Oncology 2017;92:50-62.
Abril-Rodriguez G, Ribas A. SnapShot: immune checkpoint inhibitors. Cancer Cell 2017;31:848-848.
Zhao X, Cao M, Lu Z, Wang T, Ren Y, Liu C, et al. Small-molecule inhibitor sorafenib regulates immunoreactions by inducing survival and differentiation of bone marrow cells. Innate Immun 2016;22:493-502.
Chen ML, Yan BS, Lu WC, Chen MH, Yu SL, Yang PC, et al. Sorafenib relieves cell-intrinsic and cell-extrinsic inhibitions of effector T cells in tumor microenvironment to augment antitumor immunity. Int J Cancer 2014;134:319-331.
Cao M, Xu Y, Youn JI, Cabrera R, Zhang X, Gabrilovich D, et al. Kinase inhibitor sorafenib modulates immunosuppressive cell populations in a murine liver cancer model. Lab Invest 2011;91:598-608.
Busse A, Asemissen AM, Nonnenmacher A, Braun F, Ochsenreither S, Stather D, et al. Immunomodulatory effects of sorafenib on peripheral immune effector cells in metastatic renal cell carcinoma. Eur J Cancer 2011;47:690-696.
Sonntag R, Gassler N, Bangen JM, Trautwein C, Liedtke C. Pro-apoptotic sorafenib signaling in murine hepatocytes depends on malignancy and is associated with PUMA expression in vitro and in vivo. Cell Death Dis 2014;5:1030.
Hipp MM, Hilf N, Walter S, Werth D, Brauer KM, Radsak MP, et al. Sorafenib, but not sunitinib, affects function of dendritic cells and induction of primary immune responses. Blood 2008;111:5610-5620.
Deng YR, Liu WB, Lian ZX, Li X, Hou X. Sorafenib inhibits macrophage-mediated epithelial-mesenchymal transition in hepatocellular carcinoma. Oncotarget 2016;7:38292-38305.
Sprinzl MF, Puschnik A, Schlitter AM, Schad A, Ackermann K, Esposito I, et al. Sorafenib inhibits macrophage-induced growth of hepatoma cells by interference with insulin-like growth factor-1 secretion. J Hepatol 2015;62:863-870.
Krusch M, Salih J, Schlicke M, Baessler T, Kampa KM, Mayer F, et al. The kinase inhibitors sunitinib and sorafenib differentially affect NK cell antitumor reactivity in vitro. J Immunol 2009;183:8286-8294.
Sprinzl MF, Reisinger F, Puschnik A, Ringelhan M, Ackermann K, Hartmann D, et al. Sorafenib perpetuates cellular anticancer effector functions by modulating the crosstalk between macrophages and natural killer cells. Hepatology 2013;57:2358-2368.
Sun C, Sun HY, Xiao WH, Zhang C, Tian ZG. Natural killer cell dysfunction in hepatocellular carcinoma and NK cell-based immunotherapy. Acta Pharmacol Sin 2015;36:1191-1199.
Zeromski J, Mozer-Lisewska I, Kaczmarek M, Kowala-Piaskowska A, Sikora J. NK cells prevalence, subsets and function in viral hepatitis C. Arch Immunol Ther Exp 2011;59:449-455.
Stahl S, Sacher T, Bechtold A, Protzer U, Ganss R, Hammerling GJ, et al. Tumor agonist peptides break tolerance and elicit effective CTL responses in an inducible mouse model of hepatocellular carcinoma. Immunol Lett 2009;123:31-37.
Ries CH, Cannarile MA, Hoves S, Benz J, Wartha K, Runza V, et al. Targeting tumor-associated macrophages with anti-CSF-1R antibody reveals a strategy for cancer therapy. Cancer Cell 2014;25:846-859.
Runge A, Hu J, Wieland M, Bergeest JP, Mogler C, Neumann A, et al. An inducible hepatocellular carcinoma model for preclinical evaluation of antiangiogenic therapy in adult mice. Cancer Res 2014;74:4157-4169.
Schneider KS, Gross CJ, Dreier RF, Saller BS, Mishra R, Gorka O, et al. The inflammasome drives GSDMD-independent secondary pyroptosis and IL-1 release in the absence of caspase-1 protease activity. Cell Rep 2017;21:3846-3859.
Gotink KJ, Verheul HM. Anti-angiogenic tyrosine kinase inhibitors: what is their mechanism of action? Angiogenesis 2010;13:1-14.
Yada M, Masumoto A, Motomura K, Tajiri H, Morita Y, Suzuki H, et al. Indicators of sorafenib efficacy in patients with advanced hepatocellular carcinoma. World J Gastroenterol 2014;20:12581-12587.
Rimola J, Diaz-Gonzalez A, Darnell A, Varela M, Pons F, Hernandez-Guerra M, et al. Complete response under sorafenib in patients with hepatocellular carcinoma: relationship with dermatologic adverse events. Hepatology 2017;10:1002.
Reig M, Torres F, Rodriguez-Lope C, Forner A, Llarch N, Rimola J, et al. Early dermatologic adverse events predict better outcome in HCC patients treated with sorafenib. J Hepatol 2014;61:318-324.
Branco F, Alencar RS, Volt F, Sartori G, Dode A, Kikuchi L, et al. The impact of early dermatologic events in the survival of patients with hepatocellular carcinoma treated with sorafenib. Ann Hepatol 2017;16:263-268.
Lohmeyer J, Nerreter T, Dotterweich J, Einsele H, Seggewiss-Bernhardt R. Sorafenib paradoxically activates the RAS/RAF/ERK pathway in polyclonal human NK cells during expansion and thereby enhances effector functions in a dose- and time-dependent manner. Clin Exp Immunol 2018;193:64-72.
Ho V, Lim TS, Lee J, Steinberg J, Szmyd R, Tham M, et al. TLR3 agonist and sorafenib combinatorial therapy promotes immune activation and controls hepatocellular carcinoma progression. Oncotarget 2015;6:27252-27266.
Levy EM, Roberti MP, Mordoh J. Natural killer cells in human cancer: from biological functions to clinical applications. J Biomed Biotechnol 2011;2011:676198.
Chew V, Tow C, Teo M, Wong HL, Chan J, Gehring A, et al. Inflammatory tumour microenvironment is associated with superior survival in hepatocellular carcinoma patients. J Hepatol 2010;52:370-379.
Maltez VI, Tubbs AL, Cook KD, Aachoui Y, Falcone EL, Holland SM, et al. Inflammasomes coordinate pyroptosis and natural killer cell cytotoxicity to clear infection by a ubiquitous environmental bacterium. Immunity 2015;43:987-997.
Tomuleasa C, Giannelli G, Cucuianu A, Aldea M, Paradiso A, Berindan-Neagoe I. Interplay between cancer cells, macrophages and natural killer cells may actually decide the outcome of therapy with sorafenib. Hepatology 2014;60:430.
Mattina J, MacKinnon N, Henderson VC, Fergusson D, Kimmelmann J. Design and reporting of targeted anticancer preclinical studies: a meta-analysis of animal studies investigating sorafenib antitumor efficacy. Cancer Res 2016;76:4627-4636.
Strumberg D, Richly H, Hilger RA, Schleucher N, Korfee S, Tewes M, et al. Phase I clinical and pharmacokinetic study of the novel Raf kinase and vascular endothelial growth factor receptor inhibitor BAY 43-9006 in patients with advanced refractory solid tumors. J Clin Oncol 2005;23:965-972.
Hoshino-Yoshino A, Kato M, Nakano K, Ishigai M, Kudo T, Ito K. Bridging from preclinical to clinical studies for tyrosine kinase inhibitors based on pharmacokinetics/pharmacodynamics and toxicokinetics/toxicodynamics. Drug Metab Pharmacokinet 2011;26:612-620.
Miao EA, Rajan JV, Aderem A. Caspase-1-induced pyroptotic cell death. Immunol Rev 2011;243:206-214.
Shi J, Gao W, Shao F. Pyroptosis: gasdermin-mediated programmed necrotic cell death. Trends Biochem Sci 2017;42:245-254.
Blankenstein T. Do autochthonous tumors interfere with effector T cell responses? Semin Cancer Biol 2007;17:267-274.
Chen Y, Ramjiawan RR, Reiberger T, Ng MR, Hato T, Huang Y, et al. CXCR43 inhibition in tumor microenvironment facilitates anti-programmed death receptor-1 immunotherapy in sorafenib-treated hepatocellular carcinoma in mice. Hepatology 2015;61:1591-1602.
Bubenik J. Tumour MHC class I downregulation and immunotherapy (Review). Oncol Rep 2003;10:2005-2008.
Kohga K, Takehara T, Tatsumi T, Ishida H, Miyagi T, Hosui A, et al. Sorafenib inhibits the shedding of major histocompatibility complex class I-related chain A on hepatocellular carcinoma cells by down-regulating a disintegrin and metalloproteinase 9. Hepatology 2010;51:1264-1273.
Yu M, Li Z. Natural killer cells in hepatocellular carcinoma: current status and perspectives for future immunotherapeutic approaches. Front Med 2017;11:509-521.
Hosseinzadeh F, Verdi J, Ai J, Hajighasemlou S, Seyhoun I, Parvizpour F, et al. Combinational immune-cell therapy of natural killer cells and sorafenib for advanced hepatocellular carcinoma: a review. Cancer Cell Int 2018;18:133.
Raoul JL, Kudo M, Finn RS, Edeline J, Reig M, Galle PR. Systemic therapy for intermediate and advanced hepatocellular carcinoma: sorafenib and beyond. Cancer Treat Rev 2018;68:16-24.
Kuzuya T, Ishigami M, Ishizu Y, Honda T, Hayashi K, Ishikawa T, et al. Fever within 2 weeks of sorafenib therapy predicts favorable treatment efficacy in patients with advanced hepatocellular carcinoma. Oncology 2016;91:261-266.
Dinarello CA. The history of fever, leukocytic pyrogen and interleukin-1. Temperature (Austin) 2015;2:8-16.