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Ecto-Calreticulin is essential for an efficient immunogenic cell death stimulation in mouse melanoma

Genes & Immunity volume 20, pages 509–513 (2019)Cite this article

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Abstract

Skin melanoma remains one of the most aggressive and difficult to treat human malignancy, with an increasing incidence every year. Although surgical resection represents the best therapeutic approach, this is only feasible in cases of early diagnosis. Furthermore, the established malignancy is resistant to all therapeutic strategies employed so far, resulting in an unacceptable patient survival rate. Although the immune-mediated therapeutic approaches, based on anti-PD1 or anti-CTLA4, are very promising and under clinical trial experimentation, they could conceal not yet fully emerged pitfalls such as the development of autoimmune diseases. Therefore, alternative therapeutic approaches are still under investigation, such as the immunogenic cell death (ICD) process. Here we show that the lack of calreticulin translocation onto mouse melanoma cell membrane prevents the stimulation of an effective ICD response in vivo.

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References

  1. Coricovac D, Dehelean C, Moaca EA, Pinzaru I, Bratu T, Navolan D, et al. Cutaneous melanoma-a long road from experimental models to clinical outcome: a review. Int J Mol Sci. 2018;19:E1566 https://doi.org/10.3390/ijms19061566.

    Article  CAS  PubMed  Google Scholar 

  2. Kostine M, Stavris C, Chiche L. Opportunistic autoimmunity secondary to immunotherapy and melanoma: Back to ABCDE? Eur J Cancer. 2017;81:240–241. https://doi.org/10.1016/j.ejca.2017.03.017.

    Article  PubMed  Google Scholar 

  3. Antunes F, Corazzari M, Pereira G, Fimia GM, Piacentini M, Smaili S. Fasting boosts sensitivity of human skin melanoma to cisplatin-induced cell death. Biochem Biophys Res Commun. 2017;485:16–22. https://doi.org/10.1016/j.bbrc.2016.09.149.

    Article  CAS  PubMed  Google Scholar 

  4. Giglio P, Fimia GM, Lovat PE, Piacentini M, Corazzari M. Fateful music from a talented orchestra with a wicked conductor: Connection between oncogenic BRAF, ER stress, and autophagy in human melanoma. Mol Cell Oncol. 2015;2:e995016. https://doi.org/10.4161/23723556.2014.995016.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Corazzari M, Rapino F, Ciccosanti F, Giglio P, Antonioli M, Conti B, et al. Oncogenic BRAF induces chronic ER stress condition resulting in increased basal autophagy and apoptotic resistance of cutaneous melanoma. Cell Death Differ. 2015;22:946–58. https://doi.org/10.1038/cdd.2014.183.

    Article  CAS  PubMed  Google Scholar 

  6. Galluzzi L, Buqué A, Kepp O, Zitvogel L, Kroemer G. Immunogenic cell death in cancer and infectious disease. Nat Rev Immunol. 2016;17:97–111. https://doi.org/10.1038/nri.2016.107.

    Article  CAS  PubMed  Google Scholar 

  7. Garg AD, Romano E, Rufo N, Agostinis P. Immunogenic versus tolerogenic phagocytosis during anticancer therapy: mechanisms and clinical translation. Cell Death Differ. 2016;23:938–51. https://doi.org/10.1038/cdd.2016.5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Inoue H, Tani K. Multimodal immunogenic cancer cell death as a consequence of anticancer cytotoxic treatments. Cell Death Differ. 2014;21:39–49. https://doi.org/10.1038/cdd.2013.84.

    Article  CAS  PubMed  Google Scholar 

  9. Qin J, Kunda N, Qiao G, Calata JF, Pardiwala K, Prabhakar BS, et al. Colon cancer cell treatment with rose bengal generates a protective immune response via immunogenic cell death. Cell Death Dis. 2017;8:e2584. https://doi.org/10.1038/cddis.2016.473.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Hunger A, Medrano RF, Strauss BE. Harnessing combined p19Arf and interferon-beta gene transfer as an inducer of immunogenic cell death and mediator of cancer immunotherapy. Cell Death Dis. 2017;8:e2784. https://doi.org/10.1038/cddis.2017.201.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Garg AD, More S, Rufo N, Mece O, Sassano ML, Agostinis P, et al. Trial watch: immunogenic cell death induction by anticancer chemotherapeutics. Oncoimmunology. 2017;6:e1386829. https://doi.org/10.1080/2162402X.2017.1386829.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Martins I, Wang Y, Michaud M, Ma Y, Sukkurwala AQ, Shen S, et al. Molecular mechanisms of ATP secretion during immunogenic cell death. Cell Death Differ. 2014;21:79–91. https://doi.org/10.1038/cdd.2013.75.

    Article  CAS  PubMed  Google Scholar 

  13. Yamazaki T, Hannani D, Poirier-Colame V, Ladoire S, Locher C, Sistigu A, et al. Defective immunogenic cell death of HMGB1-deficient tumors: compensatory therapy with TLR4 agonists. Cell Death Differ. 2014;21:69–78. https://doi.org/10.1038/cdd.2013.72.

    Article  CAS  PubMed  Google Scholar 

  14. Kepp O, Senovilla L, Vitale I, Vacchelli E, Adjemian S, Agostinis P, et al. Consensus guidelines for the detection of immunogenic cell death. Oncoimmunology. 2014;3:e955691. https://doi.org/10.4161/21624011.2014.955691.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Giglio P, Gagliardi M, Tumino N, Antunes F, Smaili S, Cotella D, et al. PKR and GCN2 stress kinases promote an ER stress-independent eIF2α phosphorylation responsible for calreticulin exposure in melanoma cells. Oncoimmunology. 2018;7:e1466765. https://doi.org/10.1080/2162402X.2018.1466765.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Galluzzi L, Vitale I, Aaronson SA, Abrams JM, Adam D, Agostinis P, et al. Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on CellDeath 2018. Cell Death Differ. 2018;25:486–541. https://doi.org/10.1038/s41418-017-0012-4.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Panaretakis T, Joza N, Modjtahedi N, Tesniere A, Vitale I, Durchschlag M, et al. The co-translocation of ERp57 and calreticulin determines the immunogenicity of cell death. Cell Death Differ. 2008;15:1499–509. https://doi.org/10.1038/cdd.2008.67.

    Article  CAS  PubMed  Google Scholar 

  18. Pagliarini V, Giglio P, Bernardoni P, De Zio D, Fimia GM, Piacentini M, et al. Downregulation of E2F1 during ER stress is required to induce apoptosis. J Cell Sci. 2015;128:1166–79. https://doi.org/10.1242/jcs.164103.

    Article  CAS  PubMed  Google Scholar 

  19. Tesniere A, Schlemmer F, Boige V, Kepp O, Martins I, Ghiringhelli F; et al. Immunogenic death of colon cancer cells treated with oxaliplatin. Oncogene. 2010;29:482–91. https://doi.org/10.1038/onc.2009.356.

    Article  CAS  PubMed  Google Scholar 

  20. Duewell P, Steger A, Lohr H, Bourhis H, Hoelz H, Kirchleitner SV, et al. RIG-I-like helicases induce immunogenic cell death of pancreatic cancer cells and sensitize tumors toward killing by CD8(+) T cells. CellDeath Differ. 2014;21:1825–37. https://doi.org/10.1038/cdd.2014.96.

    Article  CAS  Google Scholar 

  21. Tufi R, Panaretakis T, Bianchi K, Criollo A, Fazi B, Di Sano F, et al. Reduction of endoplasmic reticulum Ca2+ levels favors plasma membrane surface exposure of calreticulin. Cell Death Differ. 2008;15:274–82. https://doi.org/10.1038/sj.cdd.4402275.

    Article  CAS  PubMed  Google Scholar 

  22. Kepp O, Semeraro M, Bravo-San Pedro JM, Bloy N, Buqué A, Huang X, et al. eIF2α phosphorylation as a biomarker of immunogenic cell death. Semin Cancer Biol. 2015;33:86–92. https://doi.org/10.1016/j.semcancer.2015.02.004.

    Article  CAS  PubMed  Google Scholar 

  23. Bezu L, Sauvat A, Humeau J, Gomes-da-Silva LC, Iribarren K, Forveille S, et al. eIF2α phosphorylation is pathognomonic for immunogenic cell death. Cell Death Differ. 2018;25:1375–1393. https://doi.org/10.1038/s41418-017-0044-9.

    Article  CAS  PubMed  Google Scholar 

  24. Wiersma VR, Michalak M, Abdullah TM, Bremer E, Eggleton P. Mechanisms of translocation of ER chaperones to the cell surface and immunomodulatory roles in cancer and autoimmunity. Front Oncol. 2015;29:7. https://doi.org/10.3389/fonc.2015.00007. eCollection 2015

    Article  Google Scholar 

  25. Panaretakis T, Kepp O, Brockmeier U, Tesniere A, Bjorklund AC, Chapman DC, et al. Mechanisms of preapoptotic calreticulin exposure in immunogenic cell death. EMBO J. 2009;28:578–90. https://doi.org/10.1038/emboj.2009.1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Kim HS, Kim TJ.Yoo YM, Melatonin combined with endoplasmic reticulum stress induces cell death via the PI3K/Akt/mTOR pathway in B16F10 melanoma cells. 2014; 9:e92627. https://doi.org/10.1371/journal.pone.0092627.

    Article  Google Scholar 

  27. Oliverio S, Corazzari M, Sestito C, Piredda L, Ippolito G, Piacentini M. The spermidine analogue GC7 (N1-guanyl-1,7-diamineoheptane) induces autophagy through a mechanism not involving the hypusination of eIF5A. Amino Acids. 2014;46:2767–76. https://doi.org/10.1007/s00726-014-1821-0.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported in part by grants from the Telethon Foundation (GEP12072), AIRC (IG2014 n. 15244 to MP), the Italian Ministry of University and Research (FIRB Accordi di Programma 2011), the Italian Ministry of Health (Ricerca Corrente and Ricerca Finalizzata), Fondazione Fibrosi Cistica (Progetto FFC#8/2015).

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Author notes

  1. These authors contributed equally: Giglio Paola, Gagliardi Mara

Authors and Affiliations

  1. Department of Epidemiology, National Institute for Infectious Diseases ‘L. Spallanzani’, Rome, Italy

    Paola Giglio & Mauro Piacentini

  2. Department of Biology, University of Rome ‘Tor Vergata’, Rome, Italy

    Mara Gagliardi & Mauro Piacentini

  3. Department of Biology, Centro Servizi Interdipartimentale-STA, University of Rome ‘Tor Vergata’, Rome, Italy

    Roberta Bernardini & Maurizio Mattei

  4. Department of Health Science (DISS), University of ‘Piemonte Orientale’, Novara, Italy

    Mara Gagliardi, Diego Cotella, Claudio Santoro & Marco Corazzari

Authors
  1. Paola Giglio
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  2. Mara Gagliardi
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  3. Roberta Bernardini
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  4. Maurizio Mattei
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  5. Diego Cotella
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  6. Claudio Santoro
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  7. Mauro Piacentini
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  8. Marco Corazzari
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Corresponding author

Correspondence to Marco Corazzari.

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Giglio, P., Gagliardi, M., Bernardini, R. et al. Ecto-Calreticulin is essential for an efficient immunogenic cell death stimulation in mouse melanoma. Genes Immun 20, 509–513 (2019). https://doi.org/10.1038/s41435-018-0047-7

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  • DOI: https://doi.org/10.1038/s41435-018-0047-7

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