| ORIGINAL ARTICLES |
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Marine natural product lepadin A as a novel inducer of immunogenic cell death via CD91-dependent pathway |
| Dalila Carbone1, Carmela Gallo1, Genoveffa Nuzzo1, Giusi Barra1, Mario Dell'Isola1, Mario Affuso2, Olimpia Follero1, Federica Albiani2, Clementina Sansone3, Emiliano Manzo1, Giuliana d'Ippolito1, Angelo Fontana1,2 |
1. Institute of Biomolecular Chemistry, Consiglio Nazionale Delle Ricerche, Via Campi Flegrei 34, Pozzuoli, 80078, Naples, Italy;
2. Department of Biology, University of Naples "Federico II", Via Cupa Nuova Cinthia 21, 80126, Naples, Italy;
3. Stazione Zoologica Anton Dohrn, Istituto Nazionale di Biologia, Ecologia e Biotecnologie Marine, University of Naples "Federico II", Villa Comunale, 80121, Naples, Italy |
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Abstract Immunogenic Cell Death (ICD) represents a mechanism of enhancing T cell-driven response against tumor cells. The process is enabled by release of damage-associated molecular patterns (DAMPs) and cytokines by dying cells. Based on molecular studies and clinical marker assessment, ICD can be a new target for cancer chemotherapy hitherto restricted to a few conventional anticancer drugs. In view of the development of small molecules in targeted cancer therapy, we reported the preliminary evidence on the role of the natural product lepadin A (1) as a novel ICD inducer. Here we describe the ICD mechanism of lepadin A (1) by proving the translocation of the protein calreticulin (CRT) to the plasma membrane of human A2058 melanoma cells. CRT exposure is an ICD marker in clinical studies and was associated with the activation of the intrinsic apoptotic pathway in A2058 cells with lepadin A (1). After the treatment, the tumour cells acquired the ability to activate dendritic cells (DCs) with cytokine release and costimulatory molecule expression that is consistent with a phenotypic profile committed to priming T lymphocytes via a CD91-dependent mechanism. The effect of lepadin A (1) was dose-dependent and comparable to the response of the chemotherapy drug doxorubicin (2), a well-established ICD inducer.
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| Keywords
Immunogenic cell death
Natural products
Anticancer
Immunotherapy
Drug discovery
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| Fund:This research was founded by the project “Antitumor Drugs and Vaccines from the Sea (ADViSE)” (B43D18000240007) and the FISR COVID Project (B53C22003560002) funded by POR Campania FESR 2014–2020. |
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Corresponding Authors:
Carmela Gallo,E-mail:carmen.gallo@icb.cnr.it
E-mail: carmen.gallo@icb.cnr.it
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Issue Date: 03 November 2023
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[1] Milone MC, Xu J, Chen S-J, Collins MA, Zhou J, Powell DJ, Melenhorst JJ. Engineering-enhanced CAR T cells for improved cancer therapy. Nat Cancer. 2021;2:780-93. https://doi.org/10.1038/s43018-021-00241-5.
[2] Franzin R, Netti GS, Spadaccino F, Porta C, Gesualdo L, Stallone G, Castellano G, Ranieri E. The use of immune checkpoint inhibitors in oncology and the occurrence of AKI where do we stand? Front Immunol. 2020. https://doi.org/10.3389/fimmu.2020.574271.
[3] Yu J, Sun H, Cao W, Song Y, Jiang Z. Research progress on dendritic cell vaccines in cancer immunotherapy. Exp Hematol Oncol. 2022;11:3. https://doi.org/10.1186/s40164-022-00257-2.
[4] Zitvogel L, Apetoh L, Ghiringhelli F, André F, Tesniere A, Kroemer G. The anticancer immune response: indispensable for therapeutic success? J Clin Invest. 2008;118:1991-2001. https://doi.org/10.1172/JCI35180.
[5] Kroemer G, Galluzzi L, Kepp O, Zitvogel L. Immunogenic cell death in cancer therapy. Annu Rev Immunol. 2013;31:51-72.
[6] Fucikova J, Kepp O, Kasikova L, Petroni G, Yamazaki T, Liu P, Zhao L, Spisek R, Kroemer G, Galluzzi L. Detection of immunogenic cell death and its relevance for cancer therapy. Cell Death Dis. 2020;11:1013.
[7] Ahmed A, Tait SWG. Targeting immunogenic cell death in cancer. Mol Oncol. 2020;14:2994-3006.
[8] Abdel-Bar HM, Walters AA, Lim Y, Rouatbi N, Qin Y, Gheidari F, Han S, Osman R, Wang JTW, Al-Jamal KT. An “eat me” combinatory nano-formulation for systemic immunotherapy of solid tumors. Theranostics. 2021;11:8738-54. https://doi.org/10.7150/thno.56936.
[9] Zhou J, Wang G, Chen Y, Wang H, Hua Y, Cai Z. Immunogenic cell death in cancer therapy: present and emerging inducers. J Cell Mol Med. 2019;23:4854-65. https://doi.org/10.1111/jcmm.14356.
[10] Liu P, Zhao L, Kepp O, Kroemer G. Quantitation of calreticulin exposure associated with immunogenic cell death. Methods Enzymol. 2020;632:1-13.
[11] Brown GC, Neher JJ. Eaten alive! cell death by primary phagocytosis: ‘phagoptosis.’ Trends Biochem Sci. 2012;37:325-32. https://doi.org/10.1016/j.tibs.2012.05.002.
[12] Diederich M. Natural compound inducers of immunogenic cell death. Arch Pharm Res. 2019;42:629-45.
[13] Sansone C, Bruno A, Piscitelli C, Baci D, Fontana A, Brunet C, Noonan DM, Albini A. Natural compounds of marine origin as inducers of immunogenic cell death (ICD): potential role for cancer interception and therapy. Cells. 2021;10:1-20.
[14] Flieswasser T, Van Loenhout J, Freire Boullosa L, Van den Eynde A, De Waele J, Van Audenaerde J, Lardon F, Smits E, Pauwels P, Jacobs J. Clinically relevant chemotherapeutics have the ability to induce immunogenic cell death in non-small cell lung cancer. Cells. 2020;9:1474. https://doi.org/10.3390/cells9061474.
[15] Ma F, He C, Wang E, Tong R. Collective asymmetric total syntheses of marine decahydroquinoline alkaloid lepadins A-E, H, and ent-I. Org Lett. 2021;23:6583-8. https://doi.org/10.1021/acs.orglett.1c02435.
[16] Gallo C, Barra G, Saponaro M, Manzo E, Fioretto L, Ziaco M, Nuzzo G, d’Ippolito G, De Palma R, Fontana A. A new bioassay platform design for the discovery of small molecules with anticancer immunotherapeutic activity. Mar Drugs. 2020. https://doi.org/10.3390/md18120604.
[17] Nuzzo G, Gallo C, Crocetta F, Romano L, Barra G, Senese G, dell’Isola M, Carbone D, Tanduo V, Albiani F, et al. Identification of the marine alkaloid lepadin A as potential inducer of immunogenic cell death. Biomolecules. 2022. https://doi.org/10.3390/biom12020246.
[18] Alves AC, Nunes C, Lima J, Reis S. Daunorubicin and doxorubicin molecular interplay with 2D membrane models. Colloids Surf B Biointerfaces. 2017;160:610-8. https://doi.org/10.1016/j.colsurfb.2017.09.058.
[19] Bezu L, Gomes-de-Silva LC, Dewitte H, Breckpot K, Fucikova J, Spisek R, Galluzzi L, Kepp O, Kroemer G. Combinatorial strategies for the induction of immunogenic cell death. Front Immunol. 2015. https://doi.org/10.3389/fimmu.2015.00187.
[20] Wang Y-J, Fletcher R, Yu J, Zhang L. Immunogenic effects of chemotherapy-induced tumor cell death. Genes Dis. 2018;5:194-203. https://doi.org/10.1016/j.gendis.2018.05.003.
[21] Liu P, Zhao L, Pol J, Levesque S, Petrazzuolo A, Pfirschke C, Engblom C, Rickelt S, Yamazaki T, Iribarren K, et al. Author correction: crizotinib-induced immunogenic cell death in non-small cell lung cancer. Nat Commun. 1883;10:1883. https://doi.org/10.1038/s41467-019-09838-y.
[22] Vigueras G, Markova L, Novohradsky V, Marco A, Cutillas N, Kostrhunova H, Kasparkova J, Ruiz J, Brabec V. A photoactivated Ir(iii) complex targets cancer stem cells and induces secretion of damage-associated molecular patterns in melanoma cells characteristic of immunogenic cell death. Inorg Chem Front. 2021;8:4696-711. https://doi.org/10.1039/D1QI00856K.
[23] Silveyra E, Bologna-Molina R, Gónzalez-Gónzalez R, Arocena M. The tissue architecture of oral squamous cell carcinoma visualized by staining patterns of wheat germ agglutinin and structural proteins using confocal microscopy. Cells. 2021;10:2466. https://doi.org/10.3390/cells10092466.
[24] Campbell KJ, Tait SW. Targeting BCL-2 regulated apoptosis in cancer. Open Biol. 2018;8:180002. https://doi.org/10.1098/rsob.180002.
[25] Tan BS, Tiong KH, Choo HL, Fei-Lei Chung F, Hii L-W, Tan SH, Yap IK, Pani S, Khor NT, Wong SF, et al. Mutant P53-R273H mediates cancer cell survival and anoikis resistance through AKT-dependent suppression of BCL2-modifying factor (BMF). Cell Death Dis. 2015;6:e1826-e1826. https://doi.org/10.1038/cddis.2015.191.
[26] Gupta G, Borglum K, Chen H. Immunogenic cell death: a step ahead of autophagy in cancer therapy. J Cancer Immunol. 2021;3:47-59. https://doi.org/10.33696/cancerimmunol.3.041.Immunogenic.
[27] Qi X, Li Q, Che X, Wang Q, Wu G. Application of regulatory cell death in cancer: based on targeted therapy and immunotherapy. Front Immunol. 2022. https://doi.org/10.3389/fimmu.2022.837293.
[28] Sun S-C. CYLD: a tumor suppressor deubiquitinase regulating NF-ΚB activation and diverse biological processes. Cell Death Differ. 2010;17:25-34. https://doi.org/10.1038/cdd.2009.43.
[29] Liang X, Lu J, Wu Z, Guo Y, Shen S, Liang J, Dong Z, Guo W. LINC00239 interacts with C-Myc promoter-binding protein-1 (MBP-1) to promote expression of C-Myc in esophageal squamous cell carcinoma. Mol Cancer Res. 2021;19:1465-75. https://doi.org/10.1158/1541-7786.MCR-20-1025.
[30] Tu CC, Kumar VB, Day CH, Kuo WW, Yeh SP, Chen RJ, Liao CR, Chen HY, Tsai FJ, Wu WJ, et al. Estrogen receptor α (ESR1) over-expression mediated apoptosis in Hep3B cells by binding with SP1 proteins. J Mol Endocrinol. 2013;51:203-12. https://doi.org/10.1530/JME-13-0085.
[31] Fabian KP, Wolfson B, Hodge JW. From immunogenic cell death to immunogenic modulation: select chemotherapy regimens induce a spectrum of immune-enhancing activities in the tumor microenvironment. Front Oncol. 2021. https://doi.org/10.3389/fonc.2021.728018.
[32] Del Prete A, Salvi V, Soriani A, Laffranchi M, Sozio F, Bosisio D, Sozzani S. Dendritic cell subsets in cancer immunity and tumor antigen sensing. Cell Mol Immunol. 2023;20:432-47. https://doi.org/10.1038/s41423-023-00990-6.
[33] Steinman RM, Nussenzweig MC, Steinman RM, Hawiger D, Nussenzweig MC. Tolerogenic dendritic cells. Annu Rev Immunol. 2003;21:685-711. https://doi.org/10.1146/annurev.immunol.21.120601.141040.
[34] Chao MP, Jaiswal S, Weissman-Tsukamoto R, Alizadeh AA, Gentles AJ, Volkmer J, Weiskopf K, Willingham SB, Raveh T, Park CY, Majeti R. Calreticulin is the dominant pro-phagocytic signal on multiple human cancers and is counterbalanced by CD47. Sci Transl Med. 2014. https://doi.org/10.1126/scitranslmed.3001375.
[35] Pawaria S, Binder RJ. CD91-dependent programming of T-helper cell responses following heat shock protein immunization. Nat Commun. 2011. https://doi.org/10.1038/ncomms1524.
[36] Peckert-maier K, Langguth P, Strack A, Stich L, Mühl-zürbes P, Kuhnt C, Drassner C, Zinser E, Wrage M, Mattner J, et al. CD83 expressed by macrophages is an important immune checkpoint molecule for the resolution of inflammation. Front Immunol. 2023. https://doi.org/10.3389/fimmu.2023.1085742.
[37] Fucikova J, Spisek R, Kroemer G, Galluzzi L. Calreticulin and cancer. Cell Res. 2021;31:5-16. https://doi.org/10.1038/s41422-020-0383-9.
[38] Schcolnik A, Bernardo C, Mandy O, Mayra J, Rivera C, Flisser A. Calreticulin in phagocytosis and cancer: opposite roles in immune response outcomes. Apoptosis. 2019;24:245-55. https://doi.org/10.1007/s10495-019-01532-0.
[39] Lamberti MJ, Nigro A, Mentucci FM, Rumie Vittar NB, Casolaro V, Dal Col J. Dendritic cells and immunogenic cancer cell death: a combination for improving antitumor immunity. Pharmaceutics. 2020;12:256. https://doi.org/10.3390/pharmaceutics12030256.
[40] Zhao L, Zhang S, Chen H, Kroemer G, Kepp O, Liu P. Interference of immunogenic chemotherapy by artificially controlled calreticulin secretion from tumor cells. Amsterdam: Elsevier; 2022. p. 99-114.
[41] Sedlacek AL, Mandoiu II, Binder RJ, Sedlacek AL, Younker TP, Zhou YJ, Borghesi L, Shcheglova T, Mandoiu II, Binder RJ. Emerging tumors CD91 on dendritic cells governs immunosurveillance of nascent, emerging tumors. JCI Insight. 2019;4: e127239.
[42] Huang FY, Lei J, Sun Y, Yan F, Chen B, Zhang L, Lu Z, Cao R, Lin YY, Wang CC, et al. Induction of enhanced immunogenic cell death through ultrasound-controlled release of doxorubicin by liposome-microbubble complexes. Oncoimmunology. 2018;7: e1446720. https://doi.org/10.1080/2162402X.2018.1446720.
[43] Kawano M, Tanaka K, Itonaga I, Iwasaki T, Miyazaki M, Ikeda S, Tsumura H. Dendritic cells combined with doxorubicin induces immunogenic cell death and exhibits antitumor effects for osteosarcoma. Oncol Lett. 2016;11:2169-75. https://doi.org/10.3892/ol.2016.4175.
[44] Pruett ST, Bushnev A, Hagedorn K, Adiga M, Haynes CA, Sullards MC, Liotta DC, Merrill AH. Thematic review series: sphingolipids. biodiversity of sphingoid bases (“Sphingosines”) and related amino alcohols. J Lipid Res. 2008;49:1621-39. https://doi.org/10.1194/jlr.R800012-JLR200.
[45] Yang W, Zhang F, Deng H, Lin L, Wang S, Kang F, Yu G, Lau J, Tian R, Zhang M, et al. Smart nanovesicle-mediated immunogenic cell death through tumor microenvironment modulation for effective photodynamic immunotherapy. ACS Nano. 2020;14:620-31. https://doi.org/10.1021/acsnano.9b07212.
[46] Cuvillier O, Nava VE, Murthy SK, Edsall LC, Levade T, Milstien S, Spiegel S. Sphingosine generation, cytochrome c release, and activation of caspase-7 in doxorubicin-induced apoptosis of MCF7 breast adenocarcinoma cells. Cell Death Differ. 2001;8:162-71. https://doi.org/10.1038/sj.cdd.4400793.
[47] Janneh AH, Ogretmen B. Targeting sphingolipid metabolism as a therapeutic strategy in cancer treatment. Cancers (Basel). 2022;14:2183. https://doi.org/10.3390/cancers14092183.
[48] Casares N, Pequignot MO, Tesniere A, Ghiringhelli F, Roux S, Chaput N, Schmitt E, Hamai A, Hervas-Stubbs S, Obeid M, et al. Caspase-dependent immunogenicity of doxorubicin-induced tumor cell death. J Exp Med. 2005;202:1691-701. https://doi.org/10.1084/jem.20050915.
[49] Vanmeerbeek I, Sprooten J, De Ruysscher D, Tejpar S, Vandenberghe P, Fucikova J, Spisek R, Zitvogel L, Kroemer G, Galluzzi L, Garg AD, et al. Trial watch?: chemotherapy-induced immunogenic cell death in immuno-oncology. Oncoimmunology. 2020. https://doi.org/10.1080/2162402X.2019.1703449.
[50] Gallo C, Manzo E, Barra G, Fioretto L, Ziaco M, Nuzzo G, D’Ippolito G, Ferrera F, Contini P, Castiglia D, et al. Sulfavant A as the first synthetic TREM2 ligand discloses a homeostatic response of dendritic cells after receptor engagement. Cell Mol Life Sci. 2022;79:369. https://doi.org/10.1007/s00018-022-04297-z.
[51] Sansone C, Pistelli L, Calabrone L, Del Mondo A, Fontana A, Festa M, Noonan DM, Albini A, Brunet C. The carotenoid diatoxanthin modulates inflammatory and angiogenesis pathways in vitro in prostate cancer cells. Antioxidants. 2023. https://doi.org/10.3390/antiox12020359. |
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