Abstract
Immunotherapies for cancers may cause severe and life-threatening cardiotoxicities. The underlying mechanisms are complex and largely elusive. Currently, there are several ongoing clinical trials based on the use of activated invariant natural killer T (iNKT) cells. The potential cardiotoxicity commonly associated with this particular immunotherapy has yet been carefully evaluated. The present study aims to determine the effect of activated iNKT cells on normal and β-adrenergic agonist (isoproterenol, ISO)-stimulated hearts. Mice were treated with iNKT stimulants, α-galactosylceramide (αGC) or its analog OCH, respectively, to determine their effect on ISO-induced cardiac injury. We showed that administration of αGC (activating both T helper type 1 (Th1)- and T helper type 2 (Th2)-liked iNKT cells) significantly accelerated the progressive cardiac injury, leading to enhanced cardiac hypertrophy and cardiac fibrosis with prominent increases in collagen deposition and TGF-β1, IL-6, and alpha smooth muscle actin expression. In contrast to αGC, OCH (mainly activating Th2-liked iNKT cells) significantly attenuated the progression of cardiac injury and cardiac inflammation induced by repeated infusion of ISO. Flow cytometry analysis revealed that αGC promoted inflammatory macrophage infiltration in the heart, while OCH was able to restrain the infiltration. In vitro coculture of αGC- or OCH-pretreated primary peritoneal macrophages with primary cardiac fibroblasts confirmed the profibrotic effect of αGC and the antifibrotic effect of OCH. Our results demonstrate that activating both Th1- and Th2-liked iNKT cells is cardiotoxic, while activating Th2-liked iNKT cells is likely cardiac protective, which has implied key differences among subpopulations of iNKT cells in their response to cardiac pathological stimulation.
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16 November 2021
A Correction to this paper has been published: https://doi.org/10.1038/s41401-021-00802-5
References
Zheng PP, Li J, Kros JM. Breakthroughs in modern cancer therapy and elusive cardiotoxicity: critical research-practice gaps, challenges, and insights. Med Res Rev. 2018;38:325–76.
Totzeck M, Schuler M, Stuschke M, Heusch G, Rassaf T. Cardio-oncology—strategies for management of cancer-therapy related cardiovascular disease. Int J Cardiol. 2019;280:163–75.
Doroshow JH. Doxorubicin-induced cardiac toxicity. N Engl J Med. 1991;324:843–5.
Roth ME, Muluneh B, Jensen BC, Madamanchi C, Lee CB. Left ventricular dysfunction after treatment with ipilimumab for metastatic melanoma. Am J Ther. 2016;23:e1925–8.
Matson DR, Accola MA, Rehrauer WM, Corliss RF. Fatal myocarditis following treatment with the PD-1 inhibitor nivolumab. J Forensic Sci. 2018;63:954–7.
Quagliariello V, Passariello M, Coppola C, Rea D, Barbieri A, Scherillo M, et al. Cardiotoxicity and pro-inflammatory effects of the immune checkpoint inhibitor pembrolizumab associated to trastuzumab. Int J Cardiol. 2019;292:171–9.
Crosby CM, Kronenberg M. Tissue-specific functions of invariant natural killer T cells. Nat Rev Immunol. 2018;18:559–74.
Salio M, Silk JD, Jones EY, Cerundolo V. Biology of CD1- and MR1-restricted T cells. Annu Rev Immunol. 2014;32:323–66.
Nagarajan NA, Kronenberg M. Invariant NKT cells amplify the innate immune response to lipopolysaccharide. J Immunol. 2007;178:2706–13.
Berzins SP, Smyth MJ, Baxter AG. Presumed guilty: natural killer T cell defects and human disease. Nat Rev Immunol. 2011;11:131–42.
Molling JW, Kolgen W, van der Vliet HJ, Boomsma MF, Kruizenga H, Smorenburg CH, et al. Peripheral blood IFN-gamma-secreting Valpha24+Vbeta11+ NKT cell numbers are decreased in cancer patients independent of tumor type or tumor load. Int J Cancer. 2005;116:87–93.
Molling JW, Langius JA, Langendijk JA, Leemans CR, Bontkes HJ, van der Vliet HJ, et al. Low levels of circulating invariant natural killer T cells predict poor clinical outcome in patients with head and neck squamous cell carcinoma. J Clin Oncol. 2007;25:862–8.
Motohashi S, Nagato K, Kunii N, Yamamoto H, Yamasaki K, Okita K, et al. A phase I-II study of alpha-galactosylceramide-pulsed IL-2/GM-CSF-cultured peripheral blood mononuclear cells in patients with advanced and recurrent non-small cell lung cancer. J Immunol. 2009;182:2492–501.
Chang DH, Osman K, Connolly J, Kukreja A, Krasovsky J, Pack M, et al. Sustained expansion of NKT cells and antigen-specific T cells after injection of alpha-galactosyl-ceramide loaded mature dendritic cells in cancer patients. J Exp Med. 2005;201:1503–17.
Uchida T, Horiguchi S, Tanaka Y, Yamamoto H, Kunii N, Motohashi S, et al. Phase I study of alpha-galactosylceramide-pulsed antigen presenting cells administration to the nasal submucosa in unresectable or recurrent head and neck cancer. Cancer Immunol Immunother. 2008;57:337–45.
Ishikawa A, Motohashi S, Ishikawa E, Fuchida H, Higashino K, Otsuji M, et al. A phase I study of alpha-galactosylceramide (KRN7000)-pulsed dendritic cells in patients with advanced and recurrent non-small cell lung cancer. Clin Cancer Res. 2005;11:1910–7.
Nieda M, Okai M, Tazbirkova A, Lin H, Yamaura A, Ide K, et al. Therapeutic activation of Valpha24+Vbeta11+ NKT cells in human subjects results in highly coordinated secondary activation of acquired and innate immunity. Blood. 2004;103:383–9.
Giaccone G, Punt CJ, Ando Y, Ruijter R, Nishi N, Peters M, et al. A phase I study of the natural killer T-cell ligand alpha-galactosylceramide (KRN7000) in patients with solid tumors. Clin Cancer Res. 2002;8:3702–9.
Motohashi S, Ishikawa A, Ishikawa E, Otsuji M, Iizasa T, Hanaoka H, et al. A phase I study of in vitro expanded natural killer T cells in patients with advanced and recurrent non-small cell lung cancer. Clin Cancer Res. 2006;12:6079–86.
Chuang HC, Sheu WH, Lin YT, Tsai CY, Yang CY, Cheng YJ, et al. HGK/MAP4K4 deficiency induces TRAF2 stabilization and Th17 differentiation leading to insulin resistance. Nat Commun. 2014;5:4602.
Xiao H, Li H, Wang JJ, Zhang JS, Shen J, An XB, et al. IL-18 cleavage triggers cardiac inflammation and fibrosis upon beta-adrenergic insult. Eur Heart J. 2018;39:60–9.
Gladka MM, Molenaar B, de Ruiter H, van der Elst S, Tsui H, Versteeg D, et al. Single-cell sequencing of the healthy and diseased heart reveals cytoskeleton-associated protein 4 as a new modulator of fibroblasts activation. Circulation. 2018;138:166–80.
Aronoff L, Epelman S, Clemente-Casares X. Isolation and identification of extravascular immune cells of the heart. J Vis Exp. 2018;23:58114.
Qu X, Liu Y, Cao D, Chen J, Liu Z, Ji H, et al. BMP10 preserves cardiac function through its dual-activation of SMAD-mediated and STAT3-mediated pathways. J Biol Chem. 2019;294:19877–88.
Zhang X, Goncalves R, Mosser DM. The isolation and characterization of murine macrophages. Curr Protoc Immunol. 2008; Chapter 14:Unit 14.1. https://doi.org/10.1002/0471142735.im1401s83.
Ando T, Ito H, Ohtaki H, Seishima M. Toll-like receptor agonists and alpha-galactosylceramide synergistically enhance the production of interferon-gamma in murine splenocytes. Sci Rep. 2013;3:2559.
Bonaca MP, Olenchock BA, Salem JE, Wiviott SD, Ederhy S, Cohen A, et al. Myocarditis in the setting of cancer therapeutics: proposed case definitions for emerging clinical syndromes in cardio-oncology. Circulation. 2019;140:80–91.
Mann DL. Innate immunity and the failing heart: the cytokine hypothesis revisited. Circ Res. 2015;116:1254–68.
Frangogiannis NG. The inflammatory response in myocardial injury, repair, and remodelling. Nat Rev Cardiol. 2014;11:255–65.
Frangogiannis NG. Cardiac fibrosis: cell biological mechanisms, molecular pathways and therapeutic opportunities. Mol Asp Med. 2019;65:70–99.
Savvatis K, Muller I, Frohlich M, Pappritz K, Zietsch C, Hamdani N, et al. Interleukin-6 receptor inhibition modulates the immune reaction and restores titin phosphorylation in experimental myocarditis. Basic Res Cardiol. 2014;109:449.
Swirski FK, Nahrendorf M. Cardioimmunology: the immune system in cardiac homeostasis and disease. Nat Rev Immunol. 2018;18:733–44.
Pinto AR, Ilinykh A, Ivey MJ, Kuwabara JT, D’Antoni ML, Debuque R, et al. Revisiting cardiac cellular composition. Circ Res. 2016;118:400–9.
Bajpai G, Bredemeyer A, Li W, Zaitsev K, Koenig AL, Lokshina I, et al. Tissue resident CCR2− and CCR2+ cardiac macrophages differentially orchestrate monocyte recruitment and fate specification following myocardial injury. Circ Res. 2019;124:263–78.
Dewald O, Zymek P, Winkelmann K, Koerting A, Ren G, Abou-Khamis T, et al. CCL2/monocyte chemoattractant protein-1 regulates inflammatory responses critical to healing myocardial infarcts. Circ Res. 2005;96:881–9.
Hulsmans M, Clauss S, Xiao L, Aguirre AD, King KR, Hanley A, et al. Macrophages facilitate electrical conduction in the heart. Cell. 2017;169:510–22.e20.
Van Linthout S, Miteva K, Tschope C. Crosstalk between fibroblasts and inflammatory cells. Cardiovasc Res. 2014;102:258–69.
Tan C, Tasaka H, Yu KP, Murphy ML, Karnofsky DA. Daunomycin, an antitumor antibiotic, in the treatment of neoplastic disease. Clinical evaluation with special reference to childhood leukemia. Cancer. 1967;20:333–53.
Xu X, Huang W, Heczey A, Liu D, Guo L, Wood M, et al. NKT cells coexpressing a GD2-specific chimeric antigen receptor and IL15 show enhanced in vivo persistence and antitumor activity against neuroblastoma. Clin Cancer Res. 2019;25:7126–38.
Johnson DB, Balko JM, Compton ML, Chalkias S, Gorham J, Xu Y, et al. Fulminant myocarditis with combination immune checkpoint blockade. N Engl J Med. 2016;375:1749–55.
Felker GM, Thompson RE, Hare JM, Hruban RH, Clemetson DE, Howard DL, et al. Underlying causes and long-term survival in patients with initially unexplained cardiomyopathy. N Engl J Med. 2000;342:1077–84.
Ganatra S, Carver JR, Hayek SS, Ky B, Leja MJ, Lenihan DJ, et al. Chimeric antigen receptor T-cell therapy for cancer and heart: JACC council perspectives. J Am Coll Cardiol. 2019;74:3153–63.
Ganatra S, Parikh R, Neilan TG. Cardiotoxicity of immune therapy. Cardiol Clin. 2019;37:385–97.
Neelapu SS, Tummala S, Kebriaei P, Wierda W, Gutierrez C, Locke FL, et al. Chimeric antigen receptor T-cell therapy—assessment and management of toxicities. Nat Rev Clin Oncol. 2018;15:47–62.
Miyaki E, Hiraga N, Imamura M, Uchida T, Kan H, Tsuge M, et al. Interferon alpha treatment stimulates interferon gamma expression in type I NKT cells and enhances their antiviral effect against hepatitis C virus. PLoS One. 2017;12:e0172412.
Wolf MJ, Adili A, Piotrowitz K, Abdullah Z, Boege Y, Stemmer K, et al. Metabolic activation of intrahepatic CD8+ T cells and NKT cells causes nonalcoholic steatohepatitis and liver cancer via cross-talk with hepatocytes. Cancer Cell. 2014;26:549–64.
Homma T, Kinugawa S, Takahashi M, Sobirin MA, Saito A, Fukushima A, et al. Activation of invariant natural killer T cells by alpha-galactosylceramide ameliorates myocardial ischemia/reperfusion injury in mice. J Mol Cell Cardiol. 2013;62:179–88.
Wang HX, Li WJ, Hou CL, Lai S, Zhang YL, Tian C, et al. CD1d-dependent natural killer T cells attenuate angiotensin II-induced cardiac remodelling via IL-10 signalling in mice. Cardiovasc Res. 2019;115:83–93.
Benjamin IJ, Jalil JE, Tan LB, Cho K, Weber KT, Clark WA. Isoproterenol-induced myocardial fibrosis in relation to myocyte necrosis. Circ Res. 1989;65:657–70.
Zhang G, Zhang X, Li D, Tian J, Jiang W. Long-term oral atazanavir attenuates myocardial infarction-induced cardiac fibrosis. Eur J Pharmacol. 2018;828:97–102.
Sobirin MA, Kinugawa S, Takahashi M, Fukushima A, Homma T, Ono T, et al. Activation of natural killer T cells ameliorates postinfarct cardiac remodeling and failure in mice. Circ Res. 2012;111:1037–47.
Acknowledgements
This study was funded by the National Natural Science Foundation of China (#81773742 and #81520108029 to XHL, #81703521 to YFD, and #81473260 to JZZ).
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XHL, and DYC, designed research; XC, JL, JL, WJW, YFD, SQY, and WJL, performed research; XC, SHL, YL, and DYC, analyzed data; XC, and DYC, drafted the paper; DYC, WNS, JZZ, and XHL, revised and finalized the paper. All authors contributed to and have approved the paper.
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Chen, X., Liu, J., Liu, J. et al. α-Galactosylceramide and its analog OCH differentially affect the pathogenesis of ISO-induced cardiac injury in mice. Acta Pharmacol Sin 41, 1416–1426 (2020). https://doi.org/10.1038/s41401-020-00517-z
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DOI: https://doi.org/10.1038/s41401-020-00517-z
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