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Hyperthermic intraperitoneal chemotherapy leads to an anticancer immune response via exposure of cell surface heat shock protein 90

Oncogene volume 35, pages 261–268 (2016)Cite this article

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Abstract

The occurrence of peritoneal carcinomatosis is a major cause of treatment failure in colorectal cancer and is considered incurable. However, new therapeutic approaches have been proposed, including cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (HIPEC). Although HIPEC has been effective in selected patients, it is not known how HIPEC prolongs a patient’s lifespan. Here, we have demonstrated that HIPEC-treated tumor cells induce the activation of tumor-specific T cells and lead to vaccination against tumor cells in mice. We have established that this effect results from the HIPEC-mediated exposure of heat shock protein (HSP) 90 at the plasma membrane. Inhibition or blocking of HSP90, but not HSP70, prevented the HIPEC-mediated antitumoral vaccination. Our work raises the possibility that the HIPEC procedure not only kills tumor cells but also induces an efficient anticancer immune response, therefore opening new opportunities for cancer treatment.

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References

  1. Elias D, Lefevre JH, Chevalier J, Brouquet A, Marchal F, Classe JM et al. Complete cytoreductive surgery plus intraperitoneal chemohyperthermia with oxaliplatin for peritoneal carcinomatosis of colorectal origin. J Clin Oncol 2009; 27: 681–685.

    Article  Google Scholar 

  2. Spiliotis JD . Peritoneal carcinomatosis cytoreductive surgery and HIPEC: a ray of hope for cure. Hepatogastroenterology 2010; 57: 1173–1177.

    PubMed  Google Scholar 

  3. Kroemer G, Galluzzi L, Kepp O, Zitvogel L . Immunogenic cell death in cancer therapy. Annu Rev Immunol 2013; 31: 51–72.

    Article  CAS  Google Scholar 

  4. Garg AD, Nowis D, Golab J, Vandenabeele P, Krysko DV, Agostinis P . Immunogenic cell death, DAMPs and anticancer therapeutics: an emerging amalgamation. Biochim Biophys Acta 2010; 1805: 53–71.

    CAS  Google Scholar 

  5. Lanneau D, Brunet M, Frisan E, Solary E, Fontenay M, Garrido C . Heat shock proteins: essential proteins for apoptosis regulation. J Cell Mol Med 2008; 12: 743–761.

    Article  CAS  Google Scholar 

  6. Murshid A, Gong J, Calderwood SK . The role of heat shock proteins in antigen cross presentation. Front Immunol 2012; 3: 63.

    Article  Google Scholar 

  7. Spisek R, Charalambous A, Mazumder A, Vesole DH, Jagannath S, Dhodapkar MV . Bortezomib enhances dendritic cell (DC)-mediated induction of immunity to human myeloma via exposure of cell surface heat shock protein 90 on dying tumor cells: therapeutic implications. Blood 2007; 109: 4839–4845.

    Article  CAS  Google Scholar 

  8. Pockley AG . Heat shock proteins as regulators of the immune response. Lancet 2003; 362: 469–476.

    Article  CAS  Google Scholar 

  9. Botzler C, Li G, Issels RD, Multhoff G . Definition of extracellular localized epitopes of Hsp70 involved in an NK immune response. Cell Stress Chaperones 1998; 3: 6–11.

    Article  CAS  Google Scholar 

  10. Senovilla L, Vitale I, Martins I, Tailler M, Pailleret C, Michaud M et al. An immunosurveillance mechanism controls cancer cell ploidy. Science 2012; 337: 1678–1684.

    Article  CAS  Google Scholar 

  11. Pelz JO, Vetterlein M, Grimmig T, Kerscher AG, Moll E, Lazariotou M et al. Hyperthermic intraperitoneal chemotherapy in patients with peritoneal carcinomatosis: role of heat shock proteins and dissecting effects of hyperthermia. Ann Surg Oncol 2013; 20: 1105–1113.

    Article  Google Scholar 

  12. Tsutsumi S, Scroggins B, Koga F, Lee MJ, Trepel J, Felts S et al. A small molecule cell-impermeant Hsp90 antagonist inhibits tumor cell motility and invasion. Oncogene 2008; 27: 2478–2487.

    Article  CAS  Google Scholar 

  13. Bae J, Mitsiades C, Tai YT, Bertheau R, Shammas M, Batchu RB et al. Phenotypic and functional effects of heat shock protein 90 inhibition on dendritic cell. J Immunol 2007; 178: 7730–7737.

    Article  CAS  Google Scholar 

  14. Schmitt E, Maingret L, Puig PE, Rerole AL, Ghiringhelli F, Hammann A et al. Heat shock protein 70 neutralization exerts potent antitumor effects in animal models of colon cancer and melanoma. Cancer Res 2006; 66: 4191–4197.

    Article  CAS  Google Scholar 

  15. Massey AJ, Williamson DS, Browne H, Murray JB, Dokurno P, Shaw T et al. A novel, small molecule inhibitor of Hsc70/Hsp70 potentiates Hsp90 inhibitor induced apoptosis in HCT116 colon carcinoma cells. Cancer Chemother Pharmacol 2010; 66: 535–545.

    Article  CAS  Google Scholar 

  16. Wilke CM, Wu K, Zhao E, Wang G, Zou W . Prognostic significance of regulatory T cells in tumor. Int J Cancer 2010; 127: 748–758.

    CAS  PubMed  Google Scholar 

  17. Zitvogel L, Tesniere A, Kroemer G . Cancer despite immunosurveillance: immunoselection and immunosubversion. Nat Rev Immunol 2006; 6: 715–727.

    Article  CAS  Google Scholar 

  18. Klaver YL, Hendriks T, Lomme RM, Rutten HJ, Bleichrodt RP . de Hingh IH. Intraoperative hyperthermic intraperitoneal chemotherapy after cytoreductive surgery for peritoneal carcinomatosis in an experimental model. Br J Surg 2010; 97: 1874–1880.

    Article  CAS  Google Scholar 

  19. Yang XJ, Li Y, al-shammaa Hassan AH, Yang GL, Liu SY, Lu YL et al. Cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy improves survival in selected patients with peritoneal carcinomatosis from abdominal and pelvic malignancies: results of 21 cases. Ann Surg Oncol 2009; 16: 345–351.

    Article  Google Scholar 

  20. Castellino F, Boucher PE, Eichelberg K, Mayhew M, Rothman JE, Houghton AN et al. Receptor-mediated uptake of antigen/heat shock protein complexes results in major histocompatibility complex class I antigen presentation via two distinct processing pathways. J Exp Med 2000; 191: 1957–1964.

    Article  CAS  Google Scholar 

  21. John K, Schreiber S, Kubelt J, Herrmann A, Muller P . Transbilayer movement of phospholipids at the main phase transition of lipid membranes: implications for rapid flip-flop in biological membranes. Biophys J 2002; 83: 3315–3323.

    Article  CAS  Google Scholar 

  22. Tsvetkova NM, Horvath I, Torok Z, Wolkers WF, Balogi Z, Shigapova N et al. Small heat-shock proteins regulate membrane lipid polymorphism. Proc Natl Acad Sci USA 2002; 99: 13504–13509.

    Article  CAS  Google Scholar 

  23. Kim YS, Alarcon SV, Lee S, Lee MJ, Giaccone G, Neckers L et al. Update on Hsp90 inhibitors in clinical trial. Curr Top Med Chem 2009; 9: 1479–1492.

    Article  CAS  Google Scholar 

  24. Beneteau M, Zunino B, Jacquin MA, Meynet O, Chiche J, Pradelli LA et al. Combination of glycolysis inhibition with chemotherapy results in an antitumor immune response. Proc Natl Acad Sci USA 2012; 109: 20071–20076.

    Article  CAS  Google Scholar 

  25. Sugarbaker PH, Chang D, Stuart OA . Hyperthermic intraoperative thoracoabdominal chemotherapy. Gastroenterol Res Prac 2012; 2012: 623417.

    Google Scholar 

  26. 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.

    Article  Google Scholar 

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Acknowledgements

We gratefully acknowledge the Centre Méditerranéen de Médecine Moléculaire animal room and imaging facilities. We thank Jozef Bossowski, Drs Raucoules and Benchimol, Benjamin Lefebvre and all of the operating room and surgical digestive service nurses for their help. This work was supported by the Fondation ARC (Association pour la Recherche sur le Cancer), the Agence Nationale de la Recherche (LABEX SIGNALIFE ANR-11-LABX-0028-01). CRP is supported by the Fondation ARC, LM is supported by la Ville de Nice and by Fondation pour la Recherche Medicale (FRM) and JC is supported by la Fondation de France.

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Authors and Affiliations

  1. Inserm, U1065, Centre Méditerranéen de Médecine Moléculaire (C3M), équipe “contrôle métabolique des morts cellulaires”, Nice, France

    B Zunino, C Rubio-Patiño, E Villa, O Meynet, E Proics, A Cornille, S Pommier, L Mondragón, J Chiche, M Carles & J-E Ricci

  2. Université de Nice-Sophia-Antipolis, Faculté de Médecine, Nice, France

    B Zunino, C Rubio-Patiño, E Villa, O Meynet, E Proics, A Cornille, S Pommier, L Mondragón, J Chiche, M Carles & J-E Ricci

  3. Département d’Anesthésie Réanimation, Centre Hospitalier Universitaire de Nice, Nice, France

    B Zunino, S Pommier, M Carles & J-E Ricci

  4. Centre Hospitalier Universitaire de Nice, Service de Chirurgie générale et Cancérologie Digestive, Nice, France

    J-M Bereder

Authors
  1. B Zunino
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  2. C Rubio-Patiño
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  3. E Villa
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  4. O Meynet
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  6. A Cornille
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  7. S Pommier
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  9. J Chiche
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  10. J-M Bereder
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  11. M Carles
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  12. J-E Ricci
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Corresponding author

Correspondence to J-E Ricci.

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The authors declare no conflict of interest.

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Supplementary Information accompanies this paper on the Oncogene website

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Zunino, B., Rubio-Patiño, C., Villa, E. et al. Hyperthermic intraperitoneal chemotherapy leads to an anticancer immune response via exposure of cell surface heat shock protein 90. Oncogene 35, 261–268 (2016). https://doi.org/10.1038/onc.2015.82

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  • DOI: https://doi.org/10.1038/onc.2015.82

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