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Human T lymphocyte responses against lung cancer induced by recombinant truncated mouse EGFR

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Abstract

The induction of active cellular responses against EGFR should be a promising approach for the treatment of those receptor-positive tumors. However, the immunity against EGFR is presumably difficult to elicit by vaccine based on self or syngeneic EGFR due to the immune tolerance acquired during the development in immune system. We proposed a model to break immune tolerance against self-EGFR through an altered immunogen source based on xenogeneic homologous EGFR. We have previously shown human EGFR as a xenoantigen could induce specific immune responses in mouse and cross-react with mouse EGFR, and resulted in therapeutic benefits for EGFR-positive mouse tumor. Here, we show a recombinant form of extracellular domain of mouse EGFR, in the presence of DCs, could activate human peripheral T cells to proliferate, secret IFN-γ, the induced responses could cross-react with human EGFR and kill autologous EGFR-positive lung cancer cells which could be blocked by anti-CD8 and anti-MHC class I antibody. There is no detectable cytotoxical activity against lung tissue, liver tissue and kidney tissue derived from paracancerous normal tissue. These observations suggest that antitumor immunity induced by the truncated mouse EGFR may be provoked in a cross-reaction between mouse EGFR and self-EGFR, and may provide insight into treatment of EGFR-positive tumors through induction of the autoimmune responses against EGFR.

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Abbreviations

EGFR:

Epidermal growth factor receptor

CTL:

Cytotoxic T lymphocyte

IFN-γ:

Interferon-γ

DC:

Dendritic cell

MHC:

Major histocompatibility complex

reMER:

Recombinant form of extracellular domain of mouse EGFR

reHER:

Recombinant form of extracellular domain of human EGFR

PBS:

Phosphate-buffered saline

References

  1. Blume-Jensen P, Hunter T (2001) Oncogenic kinase signaling. Nature 411:355

    Article  PubMed  CAS  Google Scholar 

  2. Yarden Y, Sliwkowski MX (2001) Untanging the ErbB signalling network. Nat Rev Mol Cell Biol 2:127

    Article  PubMed  CAS  Google Scholar 

  3. Carpenter G (1987) Receptors for epidermal growth factor and other polypeptide mitogens. Annu Rev Biochem 56:881

    Article  PubMed  CAS  Google Scholar 

  4. Mendelsohn J, Baselga J (2000) The EGF receptor family as targets for cancer therapy. Oncogene 19:6550

    Article  PubMed  CAS  Google Scholar 

  5. Grunwald V, Hidalgo M (2003) Developing inhibitors of the epidermal growth factor receptor for cancer treatment. J Natl Cancer Inst 95:851

    Article  PubMed  Google Scholar 

  6. Mishima K, Johns TG, Luwor RB, Scott AM, Stockert E, Jungbluth AA, Ji XD, Suvarna P, Voland JR, Old LJ, Huang HJ, Cavenee WK (2001) Growth suppression of intracranial xenografted glioblastomas overexpressing mutant epidermal growth factor receptors by systemic administration of monoclonal antibody (mAb) 806, a novel monoclonal antibody directed to the receptor. Cancer Res 61:5349

    PubMed  CAS  Google Scholar 

  7. Lu Y, Wei YQ, Tian L, Zhao X, Yang L, Hu B, Kan B, Wen YJ, Liu F, Deng HX, Li J, Mao YQ, Lei S, Huang MJ, Peng F, Jiang Y, Zhou H, Zhou LQ, Luo F (2003) Immunogene therapy of tumors with vaccine based on xenogeneic epidermal growth factor receptor. J Immunol 170: 3162

    PubMed  CAS  Google Scholar 

  8. Wei Y, Zhao X, Kariya Y, Fukata H, Teshigawara K, Uchida A (1996) Induction of autologous tumor killing by heat treatment of fresh human tumor cells: involvement of γδ T cells and heat shock protein 70. Cancer Res 56:1104

    PubMed  CAS  Google Scholar 

  9. Zhao X, Wei YQ, Peng ZL (2001) Induction of T cell responses against autologous ovarian tumors with whole tumor cell lysate-plused dendritic cells. Immunol Invest 30:33

    Article  PubMed  CAS  Google Scholar 

  10. Hu B, Tian L, Lu Y, Yang L, Zhao X, Liu JY, Wei YQ (2003) Expression, purification and refolding of extracellular domain of mouse epidermal growth factor receptor (in Chinese). J Biomed Eng 20:264

    CAS  Google Scholar 

  11. Li Y, Wang MN, Li H, King KD, Bassi R, Sun H, Santiago A, Hooper AT, Bohlen P, Hicklin DJ (2002) Active immunization against the vascular endothelial growth factor receptor flk1 inhibits tumor angiogenesis and metastasis. J Exp Med 195:1575

    Article  PubMed  CAS  Google Scholar 

  12. Hartig CV, Haller GW, Sachs DH, Kuhlenschmidt S, Heeger PS (2000) Naturally developing memory T cell xenoreactivity to Swine antigens in human peripheral blood lymphocytes. J Immunol 164:2790

    PubMed  CAS  Google Scholar 

  13. Jager E, Nagata Y, Gnjatic S, Wada H, Stockert E, Karbach J, Dunbar PR, Lee SY, Jungbluth A, Jager D, Arand M, Ritter G, Cerundolo V, Dupont B, Chen YT, Old LJ, Knuth A (2000) Monitoring CD8 T cell responses to NY-ESO-1: correlation of humoral and cellular immune responses. Proc Natl Acad Sci USA 97:4760

    Article  PubMed  CAS  Google Scholar 

  14. Zhao X, Wei YQ, Kariya Y, Teshigawara K, Uchida A (1995) Accumulation of gamma/delta T cells in human dysgerminoma and seminoma: roles in autologous tumor killing and granuloma formation. Immunol Invest 24:607

    Article  PubMed  CAS  Google Scholar 

  15. Romagnani S (1997) The Th1/Th2 paradigm. Immunol Today 18:263

    Article  PubMed  CAS  Google Scholar 

  16. Mosmann TR, Sad S (1996) The expanding universe of T-cell subsets: Th1, Th2 and more. Immunol Today 17:138

    Article  PubMed  CAS  Google Scholar 

  17. Robey IF, Edmundson AB, Schluter SF, Yocum DE, Marchalonis JJ (2002) Specificity mapping of human anti-T cell receptor monoclonal natural antibodies: defining the properties of epitope recognition promiscuity. FASEB J 16:642

    Article  PubMed  CAS  Google Scholar 

  18. Joshi SK, Suresh PR, Chauhan VS (2001) Flexibility in MHC and TCR recognition: degenerate specificity at the T cell level in recognition of promiscuous Th epitopes exhibiting no primary sequence homology. J Immunol 166:6693

    PubMed  CAS  Google Scholar 

  19. Goldrath AW, Bevan MJ (1999) Selecting and maintaining a diverse T-cell repertoire. Nature 402:255

    Article  PubMed  CAS  Google Scholar 

  20. Surh CD, Sprent J (2000) Homeostatic T cell proliferation: how far can T cells be activated to self-ligands? J Exp Med 192:F9

    Article  PubMed  CAS  Google Scholar 

  21. Kreuwel HT, Sherman LA (2001) The T-cell repertoire available for recognition of self-antigens. Curr Opin Immunol 13:639

    Article  PubMed  CAS  Google Scholar 

  22. Lo WF, Woods AS, DeCloux A, Cotter RJ, Metcalf ES, Soloski MJ (2000) Molecular mimicry mediated by MHC class Ib molecules after infection with gram-negative pathogens. Nat Med 6:215

    Article  PubMed  CAS  Google Scholar 

  23. Misko IS, Cross SM, Khanna R, Elliott SL, Schmidt C, Pye SJ, Silins SL (1999) Crossreactive recognition of viral, self, and bacterial peptide ligands by human class I-restricted cytotoxic T lymphocyte clonotypes: implications for molecular mimicry in autoimmune disease. Proc Natl Acad Sci USA 96:2279

    Article  PubMed  CAS  Google Scholar 

  24. Davies JM (2000) Introduction: epitope mimicry as a component cause of autoimmune disease. Cell Mol Life Sci 57:523

    Article  PubMed  CAS  Google Scholar 

  25. Liblau RS, Wong FS, Mars LT, Santamaria P (2002) Autoreactive CD8 cells in organ-specific autoimmunity: emerging targets for therapeutic intervention. Immunity 17:1

    Article  PubMed  CAS  Google Scholar 

  26. Morgan DJ, Kreuwel HT, Fleck S, Levitsky HI, Pardoll DM, Sherman LA (1998) Activation of low avidity CTL specific for a self epitope results in tumor rejection but not autoimmunity. J Immunol 160:643

    PubMed  CAS  Google Scholar 

  27. Bowne WB, Srinivasan R, Wolchok JD, Hawkins WG, Blachere NE, Dyall R, Lewis JJ, Houghton AN (1999) Coupling and uncoupling of tumor immunity and autoimmunity. J Exp Med 190:1717

    Article  PubMed  CAS  Google Scholar 

  28. Overwijk WW, Lee DS, Surman DR, Irvine KR, Touloukian CE, Chan CC, Carroll MW, Moss B, Rosenberg SA, Restifo NP (1999) Vaccination with a recombinant vaccinia virus encoding a “self” antigen induces autoimmune vitiligo and tumor cell destruction in mice: requirement for CD4+ T lymphocytes. Proc Natl Acad Sci USA 96:2982

    Article  PubMed  CAS  Google Scholar 

  29. Naftzger C, Takechi Y, Kohda H, Hara I, Vijayasaradhi S, Houghton AN (1996) Immune response to a differentiation antigen induced by altered antigen: a study of tumor rejection and autoimmunity. Proc Natl Acad Sci USA 93:14809

    Article  PubMed  CAS  Google Scholar 

  30. Bronte V, Apolloni E, Ronca R, Zamboni P, Overwijk WW, Surman DR, Restifo NP, Zanovello P (2000) Genetic vaccination with “self” tyrosinase-related protein 2 causes melanoma eradication but not vitiligo. Cancer Res 60:253

    PubMed  CAS  Google Scholar 

  31. Overwijk WW, Tsung A, Irvine KR, Parkhurst MR, Goletz TJ, Tsung K, Carroll MW, Liu C, Moss B, Rosenberg SA, Restifo NP (1998) gp100/pmel 17 is a murine tumor rejection antigen: induction of “self”-reactive, tumoricidal T cells using high-affinity, altered peptide ligand. J Exp Med 188:277

    Article  PubMed  CAS  Google Scholar 

  32. Mittelman M, Neumann D, Peled A, Kanter P, Haran-Ghera N (2001) Erythropoietin induces tumor regression and antitumor immune responses in murine myeloma models. Proc Natl Acad Sci USA 98:5181

    Article  PubMed  CAS  Google Scholar 

  33. Kim JJ, Yang JS, Nottingham LK, Tang W, Dang K, Manson KH, Wyand MS, Wilson DM, Weiner DB (2001) Induction of immune responses and safety profiles in rhesus macaques immunized with a DNA vaccine expressing human prostate specific antigen. Oncogene 20:4497

    Article  PubMed  CAS  Google Scholar 

  34. Fong L, Brockstedt D, Benike C, Breen JK, Strang G, Ruegg CL, Engleman EG (2001) Dendritic cell-based xenoantigen vaccination for prostate cancer immunotherapy. J Immunol 167:7150

    PubMed  CAS  Google Scholar 

  35. Haupt K, Siegel F, Lu M, Yang D, Hilken G, Mann K, Roggendorf M, Saller B (2001) Induction of a cellular and humoral immune response against preprocalcitonin by genetic immunization: a potential new treatment for medullary thyroid carcinoma. Endocrinology 142:1017

    Article  PubMed  CAS  Google Scholar 

  36. Wei YQ, Wang QR, Zhao X, Yang L, Tian L, Lu Y, Kang B, Lu CJ, Huang MJ, Lou YY, Xiao F, He QM, Shu JM, Xie XJ, Mao YQ, Lei S, Luo F, Zhou LQ, Liu CE, Zhou H, Jiang Y, Peng F, Yuan LP, Li Q, Wu Y, Liu JY (2000) Immunotherapy of tumors with xenogeneic endothelial cells as a vaccine. Nat Med 6:1160

    Article  PubMed  CAS  Google Scholar 

  37. Wei YQ, Huang MJ, Yang L, Zhao X, Tian L, Lu Y, Shu JM, Lu CJ, Niu T, Kang B, Mao YQ, Liu F, Wen YJ, Lei S, Luo F, Zhou LQ, Peng F, Jiang Y, Liu JY, Zhou H, Wang QR, He QM, Xiao F, Lou YY, Xie XJ, Li Q, Wu Y, Ding ZY, Hu B, Hu M, Zhang W (2001) Immunogene therapy of tumors with vaccine based on Xenopus homologous vascular endothelial growth factor as a model antigen. Proc Natl Acad Sci USA 98:11545

    Article  PubMed  CAS  Google Scholar 

  38. Wei YQ (2002) Immunotherapy of tumors with vaccines based on xenogeneic homologous molecules. Anticancer Drugs 13:229

    Article  PubMed  CAS  Google Scholar 

  39. Nestle FO (2000) Dendritic cell vaccination for cancer therapy. Oncogene 19:6673

    Article  PubMed  CAS  Google Scholar 

  40. Fields RC, Shimizu K, Mule J J (1998) Murine dendritic cells pulsed with whole tumor lysates mediate potent antitumor immune responses in vitro and in vivo. Proc Natl Acad Sci USA 95:9482

    Article  PubMed  CAS  Google Scholar 

  41. Fong L, Hou Y, Rivas A, Benike C, Yuen A, Fisher GA, Davis MM, Engleman EG (2001) Altered peptide ligand vaccination with Flt3 ligand expanded dendritic cells for tumor immunotherapy. Proc Natl Acad Sci USA 98:8809

    Article  PubMed  CAS  Google Scholar 

  42. Cerundolo V, Hermans IF, Salio M (2004) Dendritic cells: a journey from laboratory to clinic. Nat Immunol 5:7

    Article  PubMed  CAS  Google Scholar 

  43. Kari C, Chan TO, Rocha de Quadros M, Rodeck U (2003) Targeting the epidermal growth factor receptor in cancer: apoptosis takes center stage. Cancer Res 63:1

    PubMed  CAS  Google Scholar 

  44. Stoscheck CM, Carpenter G (1984) Down regulation of epidermal growth factor receptors: direct demonstration of receptor degradation in human fibroblasts. J Cell Biol 98:1048

    Article  PubMed  CAS  Google Scholar 

  45. Wiley HS (1988) Anomalous binding of epidermal growth factor to A431 cells is due to the effect of high receptor densities and a saturable endocytic system. J Cell Biol 107:801

    Article  PubMed  CAS  Google Scholar 

  46. French AR, Sudlow GP, Wiley HS, Lauffenburger DA (1994) Postendocytic trafficking of epidermal growth factor-receptor complexes is mediated through saturable and specific endosomal interactions. J Biol Chem 269:15749

    PubMed  CAS  Google Scholar 

  47. Kurten RC, Cadena DL, Gill GN (1996) Enhanced degradation of EGF receptors by a sorting nexin, SNX1. Science 272:1008

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

We thank Dr. Xinrong Wang for manuscript preparation. This work was supported by National Key Basic Research Program of China (2004CB518800 and 2001CB510001), Project of National Natural Sciences Foundation of China, and National 863 projects.

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Authors and Affiliations

  1. State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Guo Xue Xiang, No. 37, Chengdu, Sichuan, 610041, The People’s Republic of China

    Bing Hu, Yu-quan Wei, Ling Tian, Xia Zhao, You Lu, Yang Wu, Bing Yao & Xiao-wei Zhang

  2. Chinese National Human Genome Center at Shanghai, Guo Shou-Jing Road, No. 351, Shanghai, 201203, China

    Bing Hu

  3. Department of Gynecology and Obstetrics, Second West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan, 610041, China

    Xia Zhao

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  1. Bing Hu
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Correspondence to Yu-quan Wei.

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Hu, B., Wei, Yq., Tian, L. et al. Human T lymphocyte responses against lung cancer induced by recombinant truncated mouse EGFR. Cancer Immunol Immunother 55, 386–393 (2006). https://doi.org/10.1007/s00262-005-0028-3

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  • DOI: https://doi.org/10.1007/s00262-005-0028-3

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