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Are oncoantigens suitable targets for anti-tumour therapy?

Abstract

When a vaccine-elicited immune response is directed against oncoantigens — proteins required for the neoplastic process — the chance that the tumour will evade the vaccine should be reduced. But how can these causal oncoantigens be identified? One approach is to find tumour-associated and microenvironment-associated oncoantigens required for progression from one tumour stage to the next by comparing gene signatures isolated from the different stages of tumour progression in cancer-prone transgenic mice. Mouse oncoantigens subsequently shown to be involved in human cancer can then be validated in mouse vaccination experiments. This provides the groundwork for the rational design of cancer vaccines for clinical trials.

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Figure 1: Oncoantigens are on tumour cells and the tumour microenvironment.
Figure 2: Pipeline for the identification of onco-antigens to be used as vaccination targets.

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References

  1. Szabo, E. Selecting targets for cancer prevention: where do we go from here? Nature Rev. Cancer 6, 867–874 (2006).

    Article  CAS  Google Scholar 

  2. Kalluri, R. & Zeisberg, M. Fibroblasts in cancer. Nature Rev. Cancer 6, 392–401 (2006).

    Article  CAS  Google Scholar 

  3. Karre, K., Ljunggren, H. G., Piontek, G. & Kiessling, R. Selective rejection of H-2-deficient lymphoma variants suggests alternative immune defence strategy. Nature 319, 675–678 (1986).

    Article  CAS  PubMed  Google Scholar 

  4. Bauer, S. et al. Activation of NK cells and T cells by NKG2D, a receptor for stress-inducible MICA. Science 285, 727–729 (1999).

    Article  CAS  PubMed  Google Scholar 

  5. Nolte-'t Hoen, E. N. et al. Increased surveillance of cells in mitosis by human NK cells suggests a novel strategy for limiting tumor growth and viral replication. Blood 109, 670–673 (2007).

    Article  CAS  PubMed  Google Scholar 

  6. Merlo, L. M., Pepper, J. W., Reid, B. J. & Maley, C. C. Cancer as an evolutionary and ecological process. Nature Rev. Cancer 6, 924–935 (2006).

    Article  CAS  Google Scholar 

  7. Dunn, G. P., Bruce, A. T., Ikeda, H., Old, L. J. & Schreiber, R. D. Cancer immunoediting: from immunosurveillance to tumor escape. Nature Immunol. 3, 991–998 (2002).

    Article  CAS  Google Scholar 

  8. Finn, O. J. Premalignant lesions as targets for cancer vaccines. J. Exp. Med. 198, 1623–1626 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Lollini, P. L., Cavallo, F., Nanni, P. & Forni, G. Vaccines for tumour prevention. Nature Rev. Cancer 6, 204–216 (2006).

    Article  CAS  Google Scholar 

  10. Finn, O. J. Cancer vaccines: between the idea and the reality. Nature Rev. Immunol. 3, 630–641 (2003).

    Article  CAS  Google Scholar 

  11. Lollini, P. L. & Forni, G. Cancer immunoprevention: tracking down persistent tumor antigens. Trends Immunol. 24, 62–66 (2003).

    Article  CAS  PubMed  Google Scholar 

  12. Nanni, P. et al. p185(neu) protein is required for tumor and anchorage-independent growth, not for cell proliferation of transgenic mammary carcinoma. Int. J. Cancer 87, 186–194 (2000).

    Article  CAS  PubMed  Google Scholar 

  13. Holmgren, L. et al. A DNA vaccine targeting angiomotin inhibits angiogenesis and suppresses tumor growth. Proc. Natl Acad. Sci. USA 103, 9208–9213 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Ferrara, N., Mass, R. D., Campa, C. & Kim, R. Targeting VEGF-A to treat cancer and age-related macular degeneration. Annu. Rev. Med. 58, 491–504 (2007).

    Article  CAS  PubMed  Google Scholar 

  15. Friedman, L. M. et al. Synergistic down-regulation of receptor tyrosine kinases by combinations of mAbs: implications for cancer immunotherapy. Proc. Natl Acad. Sci. USA 102, 1915–1920 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Nanni, P. et al. Combined allogeneic tumor cell vaccination and systemic interleukin 12 prevents mammary carcinogenesis in HER-2/neu transgenic mice. J. Exp. Med. 194, 1195–1205 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Luo, W., Ko, E., Hsu, J. C., Wang, X. & Ferrone, S. Targeting melanoma cells with human high molecular weight-melanoma associated antigen-specific antibodies elicited by a peptide mimotope: functional effects. J. Immunol. 176, 6046–6054 (2006).

    Article  CAS  PubMed  Google Scholar 

  18. Yarden, Y. & Sliwkowski, M. X. Untangling the ErbB signalling network. Nature Rev. Mol. Cell Biol. 2, 127–137 (2001).

    Article  CAS  Google Scholar 

  19. Boccaccio, C. & Comoglio, P. M. Invasive growth: a MET-driven genetic programme for cancer and stem cells. Nature Rev. Cancer 6, 637–645 (2006).

    Article  CAS  Google Scholar 

  20. Zbuk, K. M. & Eng, C. Cancer phenomics: RET and PTEN as illustrative models. Nature Rev. Cancer 7, 35–45 (2007).

    Article  CAS  Google Scholar 

  21. Pedersen, I. M., Buhl, A. M., Klausen, P., Geisler, C. H. & Jurlander, J. The chimeric anti-CD20 antibody rituximab induces apoptosis in B-cell chronic lymphocytic leukemia cells through a p38 mitogen activated protein-kinase-dependent mechanism. Blood 99, 1314–1319 (2002).

    Article  CAS  PubMed  Google Scholar 

  22. Gunawardana, C. G. & Diamandis, E. P. High throughput proteomic strategies for identifying tumour-associated antigens. Cancer Lett. 249, 110–119 (2007).

    Article  CAS  PubMed  Google Scholar 

  23. Preuss, K. D., Zwick, C., Bormann, C., Neumann, F. & Pfreundschuh, M. Analysis of the B-cell repertoire against antigens expressed by human neoplasms. Immunol. Rev. 188, 43–50 (2002).

    Article  CAS  PubMed  Google Scholar 

  24. Klade, C. S. Proteomics approaches towards antigen discovery and vaccine development. Curr. Opin. Mol. Ther. 4, 216–223 (2002).

    CAS  PubMed  Google Scholar 

  25. Kreunin, P., Yoo, C., Urquidi, V., Lubman, D. M. & Goodison, S. Proteomic profiling identifies breast tumor metastasis-associated factors in an isogenic model. Proteomics 7, 299–312 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. He, Y. D. Genomic approach to biomarker identification and its recent applications. Cancer Biomark. 2, 103–133 (2006).

    Article  CAS  PubMed  Google Scholar 

  27. Narayanan, R. Bioinformatics approaches to cancer gene discovery. Methods Mol. Biol. 360, 13–31 (2007).

    CAS  PubMed  Google Scholar 

  28. Abate-Shen, C. A new generation of mouse models of cancer for translational research. Clin. Cancer Res. 12, 5274–5276 (2006).

    Article  CAS  PubMed  Google Scholar 

  29. Rangarajan, A. & Weinberg, R. A. Opinion: comparative biology of mouse versus human cells: modelling human cancer in mice. Nature Rev. Cancer 3, 952–959 (2003).

    Article  CAS  Google Scholar 

  30. Greenman, C. et al. Patterns of somatic mutation in human cancer genomes. Nature 446, 153–158 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Weitzman, J. B. & Yaniv, M. Rebuilding the road to cancer. Nature 400, 401–402 (1999).

    Article  CAS  PubMed  Google Scholar 

  32. Pillai, R. S., Bhattacharyya, S. N. & Filipowicz, W. Repression of protein synthesis by miRNAs: how many mechanisms? Trends Cell Biol. 17, 118–126 (2007).

    Article  CAS  PubMed  Google Scholar 

  33. Hossain, A., Kuo, M. T. & Saunders, G. F. Mir-17–5p regulates breast cancer cell proliferation by inhibiting translation of AIB1 mRNA. Mol. Cell Biol. 26, 8191–8201 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Uhlen, M. et al. A human protein atlas for normal and cancer tissues based on antibody proteomics. Mol. Cell Proteomics 4, 1920–1932 (2005).

    Article  CAS  PubMed  Google Scholar 

  35. Cavallo, F. et al. An integrated approach of immunogenomics and bioinformatics to identify new Tumor Associated Antigens (TAA) for mammary cancer immunological prevention. BMC Bioinformatics 6 Suppl. 4, S7 (2005).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. Barrett, T. et al. NCBI GEO: mining tens of millions of expression profiles--database and tools update. Nucleic Acids Res. 35, D760–D765 (2007).

    Article  CAS  PubMed  Google Scholar 

  37. Parkinson, H. et al. ArrayExpress-a public database of microarray experiments and gene expression profiles. Nucleic Acids Res. 35, D747–D750 (2007).

    Article  CAS  PubMed  Google Scholar 

  38. Michiels, S., Koscielny, S. & Hill, C. Prediction of cancer outcome with microarrays: a multiple random validation strategy. Lancet 365, 488–492 (2005).

    Article  CAS  PubMed  Google Scholar 

  39. Sims, A. H., Ong, K. R., Clarke, R. B. & Howell, A. High-throughput genomic technology in research and clinical management of breast cancer. Exploiting the potential of gene expression profiling: is it ready for the clinic? Breast Cancer Res. 8, 214 (2006).

    Article  PubMed  PubMed Central  Google Scholar 

  40. Lu, Y. et al. A gene expression signature predicts survival of patients with stage I non-small cell lung cancer. PLoS Med. 3, e467 (2006).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  41. Mehra, R. et al. Identification of GATA3 as a breast cancer prognostic marker by global gene expression meta-analysis. Cancer Res. 65, 11259–11264 (2005).

    Article  CAS  PubMed  Google Scholar 

  42. Miles, M. F. & Williams, R. W. Meta-analysis for microarray studies of the genetics of complex traits. Trends Biotechnol. 25, 45–47 (2007).

    Article  CAS  PubMed  Google Scholar 

  43. Hyatt, G. et al. Gene expression microarrays: glimpses of the immunological genome. Nature Immunol. 7, 686–691 (2006).

    Article  CAS  Google Scholar 

  44. van 't Veer, L. J. et al. Gene expression profiling predicts clinical outcome of breast cancer. Nature 415, 530–536 (2002).

    Article  CAS  PubMed  Google Scholar 

  45. Miller, L. D. et al. An expression signature for p53 status in human breast cancer predicts mutation status, transcriptional effects, and patient survival. Proc. Natl Acad. Sci. USA 102, 13550–13555 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Pawitan, Y. et al. Gene expression profiling spares early breast cancer patients from adjuvant therapy: derived and validated in two population-based cohorts. Breast Cancer Res. 7, R953–R964 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Calogero, R., Cordero, F, Forni, G & Cavallo, F. Inflammatory component of mammary carcinogenesis in ErbB2 transgenic mice. Breast Cancer Res. (in the press).

  48. Vlad, A. M., Kettel, J. C., Alajez, N. M., Carlos, C. A. & Finn, O. J. MUC1 immunobiology: from discovery to clinical applications. Adv. Immunol. 82, 249–293 (2004).

    Article  CAS  PubMed  Google Scholar 

  49. Carraway, K. L., 3rd, Funes, M., Workman, H. C. & Sweeney, C. Contribution of membrane mucins to tumor progression through modulation of cellular growth signaling pathways. Curr. Top. Dev. Biol. 78, 1–22 (2007).

    Article  CAS  PubMed  Google Scholar 

  50. Wei, X., Xu, H. & Kufe, D. Human mucin 1 oncoprotein represses transcription of the p53 tumor suppressor gene. Cancer Res. 67, 1853–1858 (2007).

    Article  CAS  PubMed  Google Scholar 

  51. Thompson, E. J. et al. Tyrosines in the MUC1 cytoplasmic tail modulate transcription via the extracellular signal-regulated kinase 1/2 and nuclear factor-κB pathways. Mol. Cancer Res. 4, 489–497 (2006).

    Article  CAS  PubMed  Google Scholar 

  52. Singh, P. K. & Hollingsworth, M. A. Cell surface-associated mucins in signal transduction. Trends Cell Biol. 16, 467–476 (2006).

    Article  CAS  PubMed  Google Scholar 

  53. Kohlgraf, K. G. et al. Contribution of the MUC1 tandem repeat and cytoplasmic tail to invasive and metastatic properties of a pancreatic cancer cell line. Cancer Res. 63, 5011–5020 (2003).

    CAS  PubMed  Google Scholar 

  54. Ambrosino, E. et al. Immunosurveillance of Erbb2 carcinogenesis in transgenic mice is concealed by a dominant regulatory T-cell self-tolerance. Cancer Res. 66, 7734–7740 (2006).

    Article  CAS  PubMed  Google Scholar 

  55. Rolla, S. et al. Distinct and non-overlapping T cell receptor repertoires expanded by DNA vaccination in wild-type and HER-2 transgenic BALB/c mice. J. Immunol. 177, 7626–7633 (2006).

    Article  CAS  PubMed  Google Scholar 

  56. Sakaguchi, N. et al. Altered thymic T-cell selection due to a mutation of the ZAP-70 gene causes autoimmune arthritis in mice. Nature 426, 454–460 (2003).

    Article  CAS  PubMed  Google Scholar 

  57. Disis, M. L. et al. High-titer HER-2/neu protein-specific antibody can be detected in patients with early-stage breast cancer. J. Clin. Oncol. 15, 3363–3367 (1997).

    Article  CAS  PubMed  Google Scholar 

  58. Al-Batran, S. E. et al. Intratumoral T-cell infiltrates and MHC class I expression in patients with stage IV melanoma. Cancer Res. 65, 3937–3941 (2005).

    Article  CAS  PubMed  Google Scholar 

  59. Ohlen, C. et al. CD8(+) T cell tolerance to a tumor-associated antigen is maintained at the level of expansion rather than effector function. J. Exp. Med. 195, 1407–1418 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Nanni, P. et al. Immunoprevention of mammary carcinoma in HER-2/neu transgenic mice is IFN-gamma and B cell dependent. J. Immunol. 173, 2288–2296 (2004).

    Article  CAS  PubMed  Google Scholar 

  61. Park, J. M. et al. Early role of CD4+ Th1 cells and antibodies in HER-2 adenovirus vaccine protection against autochthonous mammary carcinomas. J. Immunol. 174, 4228–4236 (2005).

    Article  CAS  PubMed  Google Scholar 

  62. Imai, K. & Takaoka, A. Comparing antibody and small-molecule therapies for cancer. Nature Rev. Cancer 6, 714–727 (2006).

    Article  CAS  Google Scholar 

  63. Terabe, M. et al. Transforming growth factor-β production and myeloid cells are an effector mechanism through which CD1d-restricted T cells block cytotoxic T lymphocyte-mediated tumor immunosurveillance: abrogation prevents tumor recurrence. J. Exp. Med. 198, 1741–1752 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Bronte, V. & Zanovello, P. Regulation of immune responses by L-arginine metabolism. Nature Rev. Immunol. 5, 641–654 (2005).

    Article  CAS  Google Scholar 

  65. Gallina, G. et al. Tumors induce a subset of inflammatory monocytes with immunosuppressive activity on CD8+ T cells. J. Clin. Invest. 116, 2777–2790 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Lustgarten, J., Dominguez, A. L. & Cuadros, C. The CD8+ T cell repertoire against Her-2/neu antigens in neu transgenic mice is of low avidity with antitumor activity. Eur. J. Immunol. 34, 752–761 (2004).

    Article  CAS  PubMed  Google Scholar 

  67. Cavallo, F., Offringa, R., van der Burg, S. H., Forni, G. & Melief, C. J. Vaccination for treatment and prevention of cancer in animal models. Adv. Immunol. 90, 175–213 (2006).

    Article  CAS  PubMed  Google Scholar 

  68. Quaglino, E. et al. Electroporated DNA vaccine clears away multifocal mammary carcinomas in her-2/neu transgenic mice. Cancer Res. 64, 2858–2864 (2004).

    Article  CAS  PubMed  Google Scholar 

  69. Quaglino, E. et al. Concordant morphologic and gene expression data show that a vaccine halts HER-2/neu preneoplastic lesions. J. Clin. Invest. 113, 709–717 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Haber, D. A. & Settleman, J. Cancer: drivers and passengers. Nature 446, 145–146 (2007).

    Article  CAS  PubMed  Google Scholar 

  71. Sjoblom, T. et al. The consensus coding sequences of human breast and colorectal cancers. Science 314, 268–274 (2006).

    Article  CAS  PubMed  Google Scholar 

  72. Pannellini, T. et al. Timely DNA vaccine combined with systemic IL-12 prevents parotid carcinomas before a dominant-negative p53 makes their growth independent of HER-2/neu expression. J. Immunol. 176, 7695–7703 (2006).

    Article  CAS  PubMed  Google Scholar 

  73. Dorrell, M. I., Aguilar, E., Scheppke, L., Barnett, F. H. & Friedlander, M. Combination angiostatic therapy completely inhibits ocular and tumor angiogenesis. Proc. Natl Acad. Sci. USA 104, 967–972 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Emens, L. A. Roadmap to a better therapeutic tumor vaccine. Int. Rev. Immunol. 25, 415–443 (2006).

    Article  CAS  PubMed  Google Scholar 

  75. Lu, H., Knutson, K. L., Gad, E. & Disis, M. L. The tumor antigen repertoire identified in tumor-bearing Neu transgenic mice predicts human tumor antigens. Cancer Res. 66, 9754–9761 (2006).

    Article  CAS  PubMed  Google Scholar 

  76. Pannellini, T., Forni, G. & Musiani, P. Immunobiology of her-2/neu transgenic mice. Breast Dis. 20, 33–42 (2004).

    Article  PubMed  Google Scholar 

  77. Astolfi, A. et al. Gene expression analysis of immune-mediated arrest of tumorigenesis in a transgenic mouse model of HER-2/neu-positive basal-like mammary carcinoma. Am. J. Pathol. 166, 1205–1216 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Astolfi, A. et al. Immune prevention of mammary carcinogenesis in HER-2/neu transgenic mice: a microarray scenario. Cancer Immunol. Immunother. 54, 599–610 (2005).

    Article  CAS  PubMed  Google Scholar 

  79. Melani, C., Chiodoni, C., Forni, G. & Colombo, M. P. Myeloid cell expansion elicited by the progression of spontaneous mammary carcinomas in c-erbB-2 transgenic BALB/c mice suppresses immune reactivity. Blood 102, 2138–2145 (2003).

    Article  CAS  PubMed  Google Scholar 

  80. Garber, K. New insights into oncogene addiction found. J. Natl Cancer Inst. 99, 264–265, 269 (2007).

    Article  PubMed  Google Scholar 

  81. Cappello, P. et al. LAG-3 enables DNA vaccination to persistently prevent mammary carcinogenesis in HER-2/neu transgenic BALB/c mice. Cancer Res. 63, 2518–25 (2003).

    CAS  PubMed  Google Scholar 

  82. Ercolini, A. M. et al. Recruitment of latent pools of high-avidity CD8(+) T cells to the antitumor immune response. J. Exp. Med. 201, 1591–1602 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Albini, A. & Sporn, M. B. The tumour microenvironment as a target for chemoprevention. Nature Rev. Cancer 7, 139–147 (2007).

    Article  CAS  Google Scholar 

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Acknowledgements

This work was supported by grants from the Italian Association for Cancer Research; the Italian Ministero dell'Università e della Ricerca; the University of Torino; the Compagnia di San Paolo, Torino; the Fondazione Denegri, Torino; the Regione Piemonte: bando regionale sulla ricerca scientifica applicata 2004; and NCEV/Nordforsk 040226 coordinator G. V. Masucci. We thank J. Iliffe for critical reading of the manuscript.

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Cavallo, F., Calogero, R. & Forni, G. Are oncoantigens suitable targets for anti-tumour therapy?. Nat Rev Cancer 7, 707–713 (2007). https://doi.org/10.1038/nrc2208

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