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HOCl Oxidation-modified CT26 Cell Vaccine Inhibits Colon Tumor Growth in a Mouse Model

  • Zhou, Rui ;
  • Huang, Wen-Jun ;
  • Ma, Cong ;
  • Zhou, Yan ;
  • Yao, Yu-Qin ;
  • Wang, Yu-Xi ;
  • Gou, Lan-Tu ;
  • Yi, Chen ;
  • Yang, Jin-Liang
  • Published : 2012.08.31

Abstract

Despite progress in elucidating mechanisms associated with colorectal cancer and improvement of treatment methods, it remains a frequent cause of death worldwide. New and more effective therapies are therefore urgently needed. Recent studies have shown that immunogenicity of whole ovarian tumor cells and subsequent T cell response were potentiated by oxidation modification with hypochlorous acid (HOCl) in vitro and ex vivo. These results prompted us to investigate the protective antitumor response with an HOCl treated CT26 colorectal cancer cell vaccine in an in vivo mouse model. Administration of HOCl modified vaccine triggered robust antitumor immunity to autologous tumor cells in mice and prolonged survival period significantly. In addition, increased necrosis and apoptosis were found in tumor tissue from the oxidation group. Interestingly, ELISPOT assays showed that specific T cell responses were not elicited in response to the immunizing cellular antigen, in contrast to raising sera antibody titer and antibody binding activity shown by ELISA assay and flow cytometry. Further evaluation of the mechanisms underlying HOCl modified vaccine mediated humoral immunity highlighted the role of antibody-dependent cell-mediated cytotoxicity. These results combined with previous studies suggest that HOCl oxidation modified whole cell vaccine has wide applicability as a cancer vaccine because it can target both T cell- and B cell-specific responses. It may thus represent a promising approach for the immunotherapy of colorectal cancer.

Keywords

HOCl;colorectal cancer;ADCC;antibody;dependent cell-mediated cytotoxicity

References

  1. Allison ME, Fearon DT (2000). Enhanced immunogenicity of aldehyde-bearing antigens: a possible link between innate and adaptive immunity. Eur J Immunol, 30, 2881-7. https://doi.org/10.1002/1521-4141(200010)30:10<2881::AID-IMMU2881>3.0.CO;2-9
  2. Anderson MM, Hazen SL, Hsu FF, et al (1997). Human neutrophils employ the myeloperoxidase-hydrogen peroxide-chloride system to convert hydroxy-amino acids into glycolaldehyde, 2-hydroxypropanal, and acrolein. A mechanism for the generation of highly reactive alphahydroxy and alpha,beta-unsaturated aldehydes by phagocytes at sites of inflammation. J Clin Invest, 99, 424-32. https://doi.org/10.1172/JCI119176
  3. Anderson MM, Requena JR, Crowley JR, et al (1999). The myeloperoxidase system of human phagocytes generates Nepsilon-(carboxymethyl)lysine on proteins: a mechanism for producing advanced glycation end products at sites of inflammation. J Clin Invest, 104, 103-13. https://doi.org/10.1172/JCI3042
  4. Callahan MK, Chaillot D, Jacquin C, et al (2002). Differential acquisition of antigenic peptides by Hsp70 and Hsc70 under oxidative conditions. J Biol Chem, 277, 33604-9. https://doi.org/10.1074/jbc.M202890200
  5. Carrasco-Marin E, Paz-Miguel JE, Lopez-Mato P, et al (1998). Oxidation of defined antigens allows protein unfolding and increases both proteolytic processing and exposes peptide epitopes which are recognized by specific T cells. Immunology, 95, 314-21. https://doi.org/10.1046/j.1365-2567.1998.00618.x
  6. Chiang CL, Ledermann JA, Rad AN, et al (2006). Hypochlorous acid enhances immunogenicity and uptake of allogeneic ovarian tumor cells by dendritic cells to cross-prime tumorspecific T cells. Cancer Immunol Immunother, 55, 1384-95. https://doi.org/10.1007/s00262-006-0127-9
  7. Chiang CL, Ledermann JA, Aitkens E, et al (2008). Oxidation of ovarian epithelial cancer cells by hypochlorous acid enhances immunogenicity and stimulates T cells that recognize autologous primary tumor. Clin Cancer Res, 14, 4898-07. https://doi.org/10.1158/1078-0432.CCR-07-4899
  8. Chiang CL, Benencia F, Coukos G (2010). Whole tumor antigen vaccines. Semin Immunol, 22, 132-43. https://doi.org/10.1016/j.smim.2010.02.004
  9. Delneste Y, Magistrelli G, Gauchat J, et al (2002). Involvement of LOX-1 in dendritic cell-mediated antigen cross-presentation. Immunity, 17, 353-62. https://doi.org/10.1016/S1074-7613(02)00388-6
  10. Grothey A (2010). Reintroduction of oxaliplatin: a viable approach to the long-term management of metastatic colorectal cancer. Oncology, 79, 389-99. https://doi.org/10.1159/000323491
  11. Harris JE, Ryan L, Hoover HC Jr, et al (2000). Adjuvant active specific immunotherapy for stage II and III colon cancer with an autologous tumor cell vaccine: Eastern Cooperative Oncology Group Study E5283. J Clin Oncol, 18, 148-57. https://doi.org/10.1200/JCO.2000.18.1.148
  12. Hazen SL, Hsu FF, Mueller DM, et al (1996). Human neutrophils employ chlorine gas as an oxidant during phagocytosis. J Clin Invest, 98, 1283-9. https://doi.org/10.1172/JCI118914
  13. Hoover HC Jr, Brandhorst JS, Peters LC, et al (1993). Adjuvant active specific immunotherapy for human colorectal cancer: 6.5-year median follow-up of a phase III prospectively randomized trial. J Clin Oncol, 11, 390-9. https://doi.org/10.1200/JCO.1993.11.3.390
  14. Jemal A, Siegel R, Ward E, et al (2008). Cancer statistics. CA Cancer J Clin, 58, 71-6. https://doi.org/10.3322/CA.2007.0010
  15. Lysaght J, Todryk S (2003). Developments in cancer vaccination. Curr Opin Investig Drugs, 4, 716-21.
  16. Marcinkiewicz J, Chain BM, Olszowska E, et al (1991). Enhancement of immunogenic properties of ovalbumin as a result of its chlorination. Int J Biochem, 23, 1393-5. https://doi.org/10.1016/0020-711X(91)90280-Z
  17. Marcinkiewicz J, Olszowska E, Olszowski S, et al (1992). Enhancement of trinitrophenyl-specific humoral response to TNP proteins as the result of carrier chlorination. Immunology, 76, 385-8.
  18. Marcinkiewicz J (1997). Neutrophil chloramines: missing links between innate and acquired immunity. Immunol Today, 18, 577-80. https://doi.org/10.1016/S0167-5699(97)01161-4
  19. Park JM, Terabe M, Sakai Y, et al (2005). Early role of CD4+ Th1 cells and antibodies in HER-2 adenovirus vaccine protection against autochthonous mammary carcinomas. J Immunol, 174, 4228-36. https://doi.org/10.4049/jimmunol.174.7.4228
  20. Penland SK, Goldberg RM (2004). Current strategies in previously untreated advanced colorectal cancer. Oncology, 18, 715-22.
  21. Piechocki MP, Pilon SA, Wei WZ (2002). Quantitative measurement of anti-ErbB-2 antibody by flow cytometry and ELISA. J Immunol Methods, 259, 33-42. https://doi.org/10.1016/S0022-1759(01)00487-2
  22. Reth M (2002). Hydrogen peroxide as second messenger in lymphocyte activation. Nat Immunol, 3, 1129-34. https://doi.org/10.1038/ni1202-1129
  23. Rovero S, Amici A, Di Carlo E, et al (2002). DNA vaccination against rat her-2/Neu p185 more effectively inhibits carcinogenesis than transplantable carcinomas in transgenic BALB/c mice. J Immunol, 165, 5133-42.
  24. Stark JM (1998). Immunological adjuvance of metabolic origin: oxidative stress, postulated impaired function of thiol proteases and immunogenicity. Scand J Immunol, 48, 475-9. https://doi.org/10.1046/j.1365-3083.1998.00443.x
  25. Suh KW, Piantadosi S, Yazdi HA, et al (1999). Treatment of liver metastases from colon carcinoma with autologous tumor vaccine expressing granulocyte-macrophage colonystimulating factor. J Surg Oncol, 72, 218-24. https://doi.org/10.1002/(SICI)1096-9098(199912)72:4<218::AID-JSO7>3.0.CO;2-N
  26. Tatla S, Woodhead V, Foreman JC, et al (1999). The role of reactive oxygen species in triggering proliferation and IL-2 secretion in T cells. Free Radic Biol Med, 26, 14-24. https://doi.org/10.1016/S0891-5849(98)00133-6
  27. Van Der Bruggen P, Zhang Y, Chaux P, et al (2002). Tumorspecific shared antigenic peptides recognized by human T cells. Immunol Rev, 188, 51-64. https://doi.org/10.1034/j.1600-065X.2002.18806.x
  28. Vermorken JB, Claessen AM, van Tinteren H, et al (1999). Active specific immunotherapy for stage II and stage III human colon cancer: a randomised trial. Lancet, 353, 345-50. https://doi.org/10.1016/S0140-6736(98)07186-4
  29. Ward S, Casey D, Labarthe MC, et al (2002). Immunotherapeutic potential of whole tumour cells. Cancer Immunol Immunother, 51, 351-7. https://doi.org/10.1007/s00262-002-0286-2