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Immunological inhibition of carcinogenesis

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Abstract

The combination of new information provided by fundamental immunology, along with the refinement of genetic engineering techniques has given scientists the capacity to produce vaccines able to inhibit the growth of most if not every transplantable tumor. However, when faced with already established tumors, vaccines fail to afford any significant protection. Many studies are underway which seek to overcome this gloomy situation. However, another possibility is to follow the indications provided by a large quantity of experimental data and to evaluate the possibility of using immunotherapy to prevent the initial stages of tumor growth. Is it possible to prevent an autologous tumor by means of a vaccination performed before tumor onset? Could antitumor vaccines be a new form of preventive medicine in the wake of Jenner, Pasteur, and other pioneers? In this paper it is our intention to review the results obtained by our laboratory in the attempt to use natural and adaptive immunity in the control of carcinogenesis. Natural immunity boosted by IL-12 and IL-2 significantly hampers the progression of mammary lesions occurring in HER-2/neu transgenic mice genetically predestined to develop lethal mammary carcinomas. Specific immunity elicited by DNA vaccination provides a much stronger inhibition of the development of mammary lesions, and a significant number of transgenic mice are tumor free at 1 year of age. These experimental data suggest the possibility of using immunity as a means of controlling preneoplastic lesions and protecting healthy persons at risk of developing cancer.

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References

  1. Agus DB, Akita RW, Fox WD, Lewis GD, Higgins B, Pisacane PI, Lofgren JA, Tindell C, Evans DP, Maiese K, Scher HI, Sliwkowski MX (2002) Targeting ligand-activated ErbB2 signaling inhibits breast and prostate tumor growth. Cancer Cell 2:127

    Article  CAS  PubMed  Google Scholar 

  2. Balkwill F, Mantovani A (2001) Inflammation and cancer: back to Virchow? Lancet 257:539

    Article  Google Scholar 

  3. Bargmann CI, Weinberg RA (1988) Increased tyrosine kinase activity associated with the protein encoded by the activated neu oncogene. Proc Natl Acad Sci U S A. 85:5394

    Google Scholar 

  4. Baselga J (2001) Herceptin alone or in combination with chemotherapy in the treatment of HER2-positive metastatic breast cancer: pivotal trials. Oncology 61:14

    Article  CAS  Google Scholar 

  5. Bishop JS, Thull NM, Matar M, Quezada A, Munger WE, Batten TL, Muller S, and Pericle F (2000) Anti-tumoral effect of a non-viral interleukin-2 gene therapy is enhanced by combination with 5-fluorouracil. Cancer Gene Ther 7:1165

    Article  CAS  PubMed  Google Scholar 

  6. Blezinger P, Freimark BD, Matar M, Wilson E, Singhal A, Min W, Nordstrom JL, Pericle F (1999) Intratracheal administration of interleukin 12 plasmid-cationic lipid complexes inhibits murine lung metastases. Hum Gene Ther 10:723

    CAS  PubMed  Google Scholar 

  7. Bocchia M, Bronte V, Colombo MP, De Vincentiis A, Di Nicola M, Forni G, Lanata L, Lemoli RM, Massaia M, Rondelli D, Zanon P, Tura S (2000) Antitumor vaccination: where we stand. Haematologica 85:1172

    CAS  PubMed  Google Scholar 

  8. Boggio K, Nicoletti G, Di Carlo E, Cavallo F, Landuzzi L, Melani C, Giovarelli M, Rossi I, Nanni P, De Giovanni C, Bouchard P, Wolf S, Modesti A, Musiani P, Lollini PL, Colombo MP, Forni G (1998) Interleukin-12 mediated prevention of spontaneous mammary adenocarcinomas in two lines of Her-2/neu transgenic mice. J Exp Med 188:589

    CAS  PubMed  Google Scholar 

  9. Boggio K., Di Carlo E., Rovero S, Cavallo F, Quaglino E, Lollini P-L, Nanni P, Nicoletti G, Wolf S, Musiani P, Forni G (2000) Ability of systemic IL-12 to hamper progressive stages of mammary carcinogenesis in Her2/neu trangenic mice. Cancer Res 60:359

    CAS  PubMed  Google Scholar 

  10. Boon T (1983) Antigenic tumor cell variants obtained with mutagens. Adv Cancer Res 39:121

    CAS  PubMed  Google Scholar 

  11. Cappello P, Triebel F, Iezzi M, Caorsi C, Quaglino E, Nanni P, Amici A, Di Carlo E, Musiani P, Giovarelli M, Forni G (2003) LAG-3 enables DNA vaccination to persistently prevent mammari carcinogenesis in HER-2/neu transgenic BALB/c mice. Cancer Res 63:2518

    CAS  PubMed  Google Scholar 

  12. Cardiff RD, Anver MR, Gusterson BA, Hennighausen L, Jensen RA, Merino MJ, Rehm S, Russo J, Tavassoli FA, Wakefield LM, Ward JM, Green JE (2000) The mammary pathology of genetically engineered mice: the consensus report and recommendations from the Annapolis meeting. Oncogene 19:968

    CAS  PubMed  Google Scholar 

  13. Cavallo F, Di Pierro F, Giovarelli M, Gulino A, Vacca A, Stoppacciaro A, Forni M, Modesti A, Forni G (1993) Protective and curative potential of vaccination with interleukin-2-gene-transfected cells from a spontaneous mouse mammary adenocarcinomas. Cancer Res 53:5067

    CAS  PubMed  Google Scholar 

  14. Cavallo F, Signorelli P, Giovarelli M, Musiani P, Modesti A, Brunda MJ, Colombo MP, Forni G (1997) Antitumor efficacy of adenocarcinoma cells engeneered to produce interleukin 12 (IL-12) or other cytokines compared with exogeneous IL-12. J Natl Cancer Inst 89:1049

    Article  CAS  PubMed  Google Scholar 

  15. Cavallo F, Di Carlo E, Butera M, Verrua R, Colombo MP, Musiani P, Forni G (1999) Immune events associated with the cure of established tumors and spontaneous metastases by local and systemic interleukin 12. Cancer Res 59:414

    CAS  PubMed  Google Scholar 

  16. Cavallo F, Quaglino E, Cifaldi L, Di Carlo E, Andrè A, Bernabei P, Musiani P, Forni G and Calogero RA (2001) IL12-activated lymphocytes influence tumor genetic programs. Cancer Res 61:3518

    CAS  PubMed  Google Scholar 

  17. Cifaldi L, Quaglino E, Di Carlo E, Musiani P, Spadaro M, Lollini P-L, Wolf S, Boggio K, Forni G, Cavallo F (2001) A light, nontoxic IL-12 protocol inhibits Her2/neu mammary carcinogenesis in BALB/c transgenic mice with established hyperplasia. Cancer Res 61:2809

    CAS  PubMed  Google Scholar 

  18. Coughlin CM, Salhany KE, Gee MS, LaTemple DC, Kotenko S, Ma X, Gri G, Wysocka M, Kim JE, Liu L, Liao F, Farber JM, Pestka S, Trinchieri G, Lee WM (1998) Tumor cell rresponse to IFN-gamma affect tumorigenicity and response to IL-12 therapy and angiogenesis. Immunity 9:25

    CAS  PubMed  Google Scholar 

  19. Coussens LM, Werb Z (2001) Inflammatory cells and cancer: think different! J Exp Med 193:F23

    Google Scholar 

  20. Curcio C, Di Carlo E, Clynes R, Smyth MJ, Boggio K, Quaglino E, Spadaro M, Colombo MP, Amici A, Lollini PL, Musiani P, Forni G (2003) Nonredundant roles of antibody, cytokines, and perforin in the eradication of established Her-2/neu carcinomas. J Clin Invest 111:1161

    Article  CAS  PubMed  Google Scholar 

  21. De Stefani A, Forni G, Ragona R, Cavallo F, Bussi M, Usai A, Badellino F, Cortesina G (2002) Improved survival with perilymphatic interleukin 2 in patients with resectable squamous cell carcinoma of the oral cavity and oropharynx. Cancer 95:90

    Article  PubMed  Google Scholar 

  22. Di Carlo E, Diodoro MG, Boggio K, Modesti A, Modesti M, Nanni P, Forni G, Musiani P (1999) Analysis of mammary carcinoma onset and progression in HER-2/neu oncogene transgenic mice reveals a lobular origin. Lab Invest 79:1261

    PubMed  Google Scholar 

  23. Dunn GP, Bruce AT, Ikeda H, Old LJ, Schreiber RD (2002) Cancer immunoediting: from immunosurveillance to tumor escape. Nat Immunol 3:991

    Article  CAS  PubMed  Google Scholar 

  24. Forni G, Lollini P-L, Musiani P, Colombo MP (2000) Immunoprevention of cancer: is the time ripe? Cancer Res 60:2571

    CAS  PubMed  Google Scholar 

  25. Garcia-Lora A, Algarra I, Collado A, Garrido F (2003) Tumour immunology, vaccination and escape strategies. Eur J Immunogenet 30:177

    Article  CAS  PubMed  Google Scholar 

  26. Grimm EA (1986) Human lymphokine-activated killer cells (LAK cells) as a potential immunotherapeutic modality. Biochim Biophys Acta 865:267

    Article  CAS  PubMed  Google Scholar 

  27. Gullick WJ, love SB,Wright C, Barnes DM, Gusterson B, Harris AL (1991) C-erbB-2 protein overexpression in breast cancer is a risk factor in patients with involved and uninvolved lymph nodes. Br J Cancer 63:434

    CAS  PubMed  Google Scholar 

  28. Hardy B, Yampolski I, Kovjazin R, Galli M, Novogrodsky A (1994) A monoclonal antibody against a human B lymphoblastoid cell line induces tumor regression in mice. Cancer Res 54:5793

    CAS  PubMed  Google Scholar 

  29. Klein G, Sjogren HO, Klein E (1960) Demonstration of resistance against methylcholanthrene-induced sarcomas in the primary autochthonous host. Cancer Res 20:1561

    CAS  Google Scholar 

  30. Koido S, Kashiwaba M, Chen D, Gendler S, Kufe D, Gong J (2000) Induction of antitumor immunity by vaccination of dendritic cells transfected with MUC1 RNA. J Immunol 165:5713

    CAS  PubMed  Google Scholar 

  31. Lane HA, Beuvink I, Motoyama AB, Daly JM, Neve RM, Hjnes NE (2000) ErbB2 potentiates breast tumor proliferation through modulation of p27 (Kip1)-Cdk2 complex formation: receptor overexpression does not determine growth dependency. Mol Cell Biol 20:3210

    Article  CAS  PubMed  Google Scholar 

  32. Lewis Phillips GD, McMurtrey AE, Schroeder K, Fendly BM (1998) Diverse activities of anti-HER2 monoclonal antibodies: from growth inhibition to induction of apoptosis. Proc Am Assoc Cancer Res 39:143

    Google Scholar 

  33. Lollini P-L, De Giovanni C, Nicoletti G, Di Carlo E, Musiani P, Nanni P, Forni G (2002) Immunoprevention of colorectal cancer: a future possibility? Gastroenterol Clin North Am 31:1001–14

    PubMed  Google Scholar 

  34. Muller WJ, Sinn E, Wallance R, Pattengale PK, Leder P (1988) Single-step induction of mammary adenocarcinoma in transgenic mice bearing the activated c-neu oncogene. Cell 54:105

    CAS  PubMed  Google Scholar 

  35. Nanni P, Nicoletti G, De Giovanni C, Landuzzi L, Di Carlo E, Cavallo F, Pupa SM, Rossi I, Colombo MP, Ricci C, Astolfi A, Musiani P, Forni G, Lollini P-L (2001) Combined allogeneic tumor cell vaccination and systemic IL-12 prevents mammary carcinogenesis in HER-2/neu transgenic mice. J Exp Med 194:1195–1205

    CAS  PubMed  Google Scholar 

  36. Noguchi Y, Jungbluth A, Richards EC, Old LJ (1996) Effect of interleukin 12 on tumor induction by 3-methylcholanthrene. Proc Natl Acad Sci U S A 93:11798–11801

    Article  CAS  PubMed  Google Scholar 

  37. Park BW, O’Rourke DM, Wang Q, Davis JG, Post A, Qian X, Greene MI (1999) Induction of the Tat-binding protein 1 gene accompanies the disabling of oncogenic erbB recepotr tyrosine kinases. Proc Natl Acad Sci U S A 96:6434

    Article  CAS  PubMed  Google Scholar 

  38. Qin Z, Richter G, Schuler T, Ibe S, Cao X, Blankenstein T (1998) B cells inhibit induction of T cell-dependent tumor immunity. Nat Med 4:627

    CAS  PubMed  Google Scholar 

  39. Rovero S, Amici A, Carlo ED, Bei R, Nanni P, Quaglino E, Porcedda P, Boggio K, Smorlesi A, Lollini PL, Landuzzi L, Colombo MP, Giovarelli M, Musiani P, Forni G (2000) DNA vaccination against rat her-2/Neu p185 more effectively inhibits carcinogenesis than transplantable carcinomas in transgenic BALB/c mice. J Immunol 165:5133

    CAS  PubMed  Google Scholar 

  40. Rovero S, Boggio K, Di Carlo E, Amici A, Quaglino E, Porcedda P, Musiani P, Forni G (2001) Insertion of the DNA for the 163–171 peptide of IL1β enables a DNA vaccine encoding p185 (neu) to inhibit mammary carcinogenesis in Her-2/neu transgenic BALB/c mice. Gene Ther 8:447

    CAS  PubMed  Google Scholar 

  41. Scott GK, Dodson JM, Montgomery PA, Johnson RM, Sarup JC, Wong WL, Ullrich A, Shepard HM, Benz CC (1991) p185her2 signal transduction in breast cancer cells. J Biol Chem 266:14300

    CAS  PubMed  Google Scholar 

  42. Shau H, Kim A, Golub H (1992) Modulation of natural killer and lymphokine-activated killer cell cytotoxicity by lactoferrin. J Leukocyte Biol 51:343

    CAS  PubMed  Google Scholar 

  43. Shih C, Padhy LC, Murray M, Weinberg RA (1981) Transforming genes of carcinomas and neuroblastomas introduced into mouse fibroblasts. Nature 290:261

    CAS  PubMed  Google Scholar 

  44. Smith RT, Landy M (eds) (1970) Immune surveillance. Academic Press, New York

  45. Smyth MJ, Trapani JA (2001) Lymphocyte-mediated immunosurveillance of epithelial cancers? Trends Immunol 22:409

    Article  CAS  PubMed  Google Scholar 

  46. Strasly M, Cavallo F, Geuna M, Mitola S, Colombo MP, Forni G, Bussolino F (2001) IL-12 inhibition of endothelial cell functions and angiogenesis depends on lymphocyte-endothelial cell cross-talk. J Immunol 166:3890

    CAS  PubMed  Google Scholar 

  47. Triebel F, Jitsukawa S, baixeras E, Roman-Roman S, Genevee C, Viegas-Pequinot E, Hercend T (1990) LAG-3, a novel lymphocyte activation gene related to CD4. J Exp Med 171:1393

    CAS  PubMed  Google Scholar 

  48. Trinchieri G (2003) Interleukin-12 and the regulation of innate resistance and adaptive immunity. Nat Rev 3:133

    Article  CAS  PubMed  Google Scholar 

  49. Yip YL, Ward RL (2002) Anti-ErbB-2 monoclonal antibodies and ErbB-2-directed vaccines. Cancer Immunol Immunother 50:569

    Article  CAS  PubMed  Google Scholar 

  50. Yip YL, Smith G, Koch J, Dubel S, Ward RL (2001) Identification of epitope regions recognized by tumor inhibitory and stimulatory anti-erbb-2 monoclonal antibodies: implications for vaccine design. J Immunol 166:5271

    CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Clinical and Biological Sciences, University of Turin, I-10043, Orbassano, Italy

    Michela Spadaro, Stefania Lanzardo, Claudia Curcio, Guido Forni & Federica Cavallo

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  1. Michela Spadaro
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  2. Stefania Lanzardo
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  3. Claudia Curcio
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  4. Guido Forni
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  5. Federica Cavallo
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Corresponding author

Correspondence to Federica Cavallo.

Additional information

This work was presented at the first Cancer Immunology and Immunotherapy Summer School, 8–13 September 2003, Ionian Village, Bartholomeio, Peloponnese, Greece.

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Spadaro, M., Lanzardo, S., Curcio, C. et al. Immunological inhibition of carcinogenesis. Cancer Immunol Immunother 53, 204–216 (2004). https://doi.org/10.1007/s00262-003-0483-7

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