Skip to main content
SpringerLink
Log in

Overcoming Self-Tolerance to Tumour Cells

  • Protocol
  • First Online:
RNA Therapeutics

Part of the book series: Methods in Molecular Biology ((MIMB,volume 629))

  • 4554 Accesses

Abstract

Over the past decade, immunotherapy has emerged as a promising alternative form of cancer treatment with the potential to eradicate tumour metastasis. However, its curative potential is in general limited by peripheral tolerance mechanisms and the elimination of self-reactive T cells via thymic negative selection. Unlike infectious challenges, tumour cells arise endogenously, and therefore the majority of tumour antigens are recognized as self. Under appropriate conditions, however, tumour reacting T cells can be activated through a mechanism of molecular mimicry, which involves the recognition of cross reactive foreign antigens mimicking tumour antigens. Moreover, dendritic cells can be reprogrammed by RNA interference to present self-antigens and activate anti-tumour T cells. This review highlights some of the strategies used to break self-tolerance against solid and blood tumour cells. Also, the possibility of reprogramming DC and/or lymphocyte functions using small interfering RNAi (siRNA) is discussed.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Protocol
USD 49.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 89.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 119.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Blattman, J.N. and Greenberg, P.D. (2004) Cancer immunotherapy: a treatment for the masses. Science, 305, 200–205.

    Article  PubMed  CAS  Google Scholar 

  2. Marincola, F.M., Jaffee, E.M., Hicklin, D.J., and Ferrone, S. (2000) Escape of human solid tumors from T-cell recognition: molecular mechanisms and functional significance. Adv Immunol, 74, 181–273.

    Article  PubMed  CAS  Google Scholar 

  3. Parkin, J. and Cohen, B. (2001) An overview of the immune system. Lancet, 357, 1777–1789.

    Article  PubMed  CAS  Google Scholar 

  4. Hogquist, K.A., Baldwin, T.A., and Jameson, S.C. (2005) Central tolerance: learning self-control in the thymus. Nat Rev Immunol, 5, 772–782.

    Article  PubMed  CAS  Google Scholar 

  5. Arnold, B., Schonrich, G., and Harmmerling, G.J. (1993) Multiple levels of peripheral tolerance. Immunol Today, 14, 12–14.

    Article  PubMed  CAS  Google Scholar 

  6. Malo, K.J. and Powrie, F. (2001) Regulatory T cells in the control of immune pathology. Nat Immunol, 2, 816–822.

    Article  Google Scholar 

  7. Mocci, S., Lafferty, K., and Howard, M. (2000) The role of autoantigen in autoimmune disease. Curr Opin Immunol, 12, 725–730.

    Article  PubMed  CAS  Google Scholar 

  8. Marrack, P., Scott-Browne, J.P., Dai, S., Gapin, L., and Kappler, J.W. (2008) Evolutionarily conserved amino acids that control TCR-MHC interaction. Annu Rev Immunol, 26, 171–203.

    Article  PubMed  CAS  Google Scholar 

  9. McDevitt, H.O. (1998) The role of MHC class II molecules in susceptibility and resistance to autoimmunity. Curr Opin Immunol, 10, 677–681.

    Article  PubMed  CAS  Google Scholar 

  10. Davis, J.M. (1997) Molecular mimicry: can epitope mimicry induce autoimmune disease?. Immunol Cell Biol, 75, 113–126.

    Article  Google Scholar 

  11. Fujinami, R.S. (2001) Can virus infections trigger autoimmune disease?. J Autoimmun, 16, 229–234.

    Article  PubMed  CAS  Google Scholar 

  12. Wucherpfennig, K.W. and Strominger, J.L. (1995) Molecular mimicry in T cell-mediated autoimmunity: viral peptides activate human T cell clones specific for myelin basic protein. Cell, 80, 695–705.

    Article  PubMed  CAS  Google Scholar 

  13. Quale, A.J., Wilson, K.B., Li, S.G., Kjeldsen-Kragh, J., Oftung, F., Shinnick, T., Sioud, M., Førre, Ø., Capra, J.D., and Natvig, J.B. (1992) Peptide recognition, T cell receptor usage and HLA restriction elements of human heat-shock protein (hsp) 60 and mycobacterial 65-kDa hsp-reactive T cell clones from rheumatoid synovial fluid. Eur J Immunol, 22, 1315–1322.

    Article  Google Scholar 

  14. Myers, L.K., Rosloniec, E.F., Cremer, M.A., and Kang, A.H. (1997) Collagen-induced arthritis, an animal model for autoimmunity. Life Sci, 61, 1861–1878.

    Article  PubMed  CAS  Google Scholar 

  15. Gordon, T.P. (1998) Determinant spreading: lessons from animal models and human disease. Immunol Rev, 164, 209–229.

    Article  PubMed  Google Scholar 

  16. Lehmann, P.V., Forsthuber, T., Miller, A., and Sercarz, E.E. (1992) Spreading of T-cell autoimmunity to cryptic determinants of an autoantigen. Nature, 359, 155–157.

    Article  Google Scholar 

  17. Lipsky, P.E. and Dorner, T. (2001) Immunoglobulin variable-region gene usage in systemic autoimmune diseases. Arthritis Rheum, 44, 2715–2727.

    Article  PubMed  Google Scholar 

  18. Gold, D.P. (1994) TCR V gene usage in autoimmunity. Curr Opin Immunol, 6, 907–912.

    Article  PubMed  CAS  Google Scholar 

  19. Sioud, M., Kjeldsen-Kragh, J., Suleyman, S., Vinje, O., Natvig, J.B., and Førre, Ø. (1992) Limited heterogeneity of T cell receptor variable region gene usage in juvenile rheumatoid arthritis synovial T cells. Eur J Immunol, 22, 2413–2418.

    Article  PubMed  CAS  Google Scholar 

  20. Butterfield, L.H., Ribas, A., Dissette, V.B., Amarnani, S.N., Vu, H.T., Oseguera, D., Wang, H.J., Elashoff, R.M., McBride, W.H., Mukherji, B., Cochran, A.J., Glaspy, J.A., and Economou, J.S. (2003) Determinant spreading associated with clinical response in dendritic cell-based immunotherapy for malignant melanoma. Clin Cancer Res, 9, 998–1008.

    PubMed  CAS  Google Scholar 

  21. Wang, R.F. and Rosenberg, S.A. (1999) Human tumor antigens for cancer vaccine development. Immunol Rev, 170, 85–100.

    Article  PubMed  CAS  Google Scholar 

  22. Houghton, A.N. (1994) Cancer antigens: immune recognition of self and altered self. J Exp Med, 180, 1–4.

    Article  PubMed  CAS  Google Scholar 

  23. Hansen, M.H., Østenstad, B., and Sioud, M. (2001) Antigen-specific IgG antibodies in stage IV long-term survival breast cancer patients. Mol Med, 7, 230–239.

    PubMed  CAS  Google Scholar 

  24. Hansen, M.H., Østenstad, B., and Sioud, M. (2001) Identification of immunogenic antigens using a phage-displayed cDNA library from an invasive ductal breast carcinoma tumour. Int J Oncol, 19, 1303–1309.

    PubMed  CAS  Google Scholar 

  25. Sioud, M. and Hansen, M.H. (2001) Profiling the immune response in patients with breast cancer by phage-displayed cDNA libraries. Eur J Immunol, 31, 716–725.

    Article  PubMed  CAS  Google Scholar 

  26. Sioud, M. (2002) How does autoimmunity cause tumor regression? A potential mechanism involving cross-reaction through epitope mimicry. Mol Med, 8, 115–119.

    PubMed  CAS  Google Scholar 

  27. Sioud, M. and Sørensen, D. (2003) Generation of an effective anti-tumor immunity after immunization with xenogeneic antigens. Eur J Immunol, 33, 38–45.

    Article  PubMed  CAS  Google Scholar 

  28. Iversen, P.O., Emanuel, P.D., and Sioud, M. (2002) Targeting Raf-1 gene expression by a DNA enzyme inhibits juvenile myelomonocytic leukemia cell growth. Blood, 99, 4147–4153.

    Article  PubMed  CAS  Google Scholar 

  29. Iversen, P.O. and Sioud, M. (1998) Modulation of granulocyte-macrophage colony-stimulating factor gene expression by a tumor necrosis factor specific ribozyme in juvenile myelomonocytic leukemic cells. Blood, 92, 4263–4268.

    PubMed  CAS  Google Scholar 

  30. Kolb, H.J., Schattenberg, A., Goldman, J.M., Hertenstein, B., Jacobsen, N., Arcese, W., Ljungman, P., Ferrant, A., Verdonck, L., Niederwieser, D., van Rhee, F., Mittermueller, J., de Witte, T., Holler, E., and Ansari, H.; European Group for Blood and Marrow Transplantation Working Party Chronic Leukemia. (1995) Graft-versus-leukemia effect of donor lymphocyte transfusions in marrow grafted patients. Blood, 86, 2041–2050.

    PubMed  CAS  Google Scholar 

  31. Stauss, H.J. (1999) Immunotherapy with CTLs restricted by nonself MHC. Immunol Today, 20, 180–183.

    Article  PubMed  CAS  Google Scholar 

  32. Amrolia, P.J., Reid, S.D., Gao, L., Schultheis, B., Dotti, G., Brenner, M.K., Melo, J.V., Goldman, J.M., and Stauss, H.J. (2003) Allorestricted cytotoxic T cells specific for human CD45 show potent antileukemic activity. Blood, 101, 1007–1014.

    Article  PubMed  CAS  Google Scholar 

  33. Gao, L., Yang, T.H., Tourdot, S., Sadovnikova, E., Hasserjian, R., and Stauss, H.J. (1999) Allo-major histocompatibility complex-restricted cytotoxic T lymphocytes engraft in bone marrow transplant recipients without causing graft-versus-host disease. Blood, 94, 2999–3006.

    PubMed  CAS  Google Scholar 

  34. Bae, J., Martinson, J.A., and Klingemann, H.G. (2005) Identification of CD19 and CD20 peptides for induction of antigen-specific CTLs against B-cell malignancies. Clin Cancer Res, 11, 1629–1638.

    Article  PubMed  CAS  Google Scholar 

  35. Heemskerk, M.H., Hoogeboom, M., de Paus, R.A., Kester, M.G., van der Hoorn, M.A., Goulmy, E., Willemze, R., and Falkenburg, J.H. (2003) Redirection of antileukemic reactivity of peripheral T lymphocytes using gene transfer of minor histocompatibility antigen HA-2-specific T-cell receptor complexes expressing a conserved alpha joining region. Blood, 102, 3530–3540.

    Article  PubMed  CAS  Google Scholar 

  36. Marijt, W.A., Heemskerk, M.H., Kloosterboer, F.M., Goulmy, E., Kester, M.G., van der Hoorn, M.A., van Luxemburg-Heys, S.A., Hoogeboom, M., Mutis, T., Drijfhout, J.W., van Rood, J.J., Willemze, R., and Falkenburg, J.H. (2003) Hematopoiesis-restricted minor histocompatibility antigens HA-1- or HA-2-specific T cells can induce complete remissions of relapsed leukemia. Proc Natl Acad Sci USA, 100, 2742–2747.

    Article  PubMed  CAS  Google Scholar 

  37. Trombetta, E.S. and Mellman, I. (2005) Cell biology of antigen processing in vitro and in vivo. Annu Rev Immunol, 23, 975–1028.

    Article  PubMed  CAS  Google Scholar 

  38. Shi, G.P., Bryant, R.A., Riese, R., Verhelst, S., Driessen, C., Li, Z., Bromme, D., Ploegh, H.L., and Chapman, H.A. (2000) Role for cathepsin F in invariant chain processing and major histocompatibility complex class II peptide loading by macrophages. J Exp Med, 191, 1177–1186.

    Article  PubMed  CAS  Google Scholar 

  39. Sadegh-Nasseri, S., Chen, M., Narayan, K., and Bouvier, M. (2008) The convergent roles of tapasin and HLA-DM in antigen presentation. Trends Immunol, 29, 141–147.

    Article  PubMed  CAS  Google Scholar 

  40. Blander, J.M. and Medzhitov, R. (2004) Regulation of phagosome maturation by signals from toll-like receptors. Science, 304, 1014–1018.

    Google Scholar 

  41. Cekaite, L., Furset, G., Hovig, E., and Sioud, M. (2007) Gene expression analysis in blood cells in response to unmodified and 2'-modified siRNAs reveals TLR-dependent and independent effects. J Mol Biol, 365, 90–108.

    Article  PubMed  CAS  Google Scholar 

  42. Furset, G. and Sioud, M. (2007) Design of bifunctional siRNAs: combining immunostimulation and gene-silencing in one single siRNA molecule. Biochem Biophys Res Commun, 352, 642–649.

    Article  PubMed  CAS  Google Scholar 

  43. Iversen, P.O., Semaeva, E., Sørensen, D.R., Wiig, H.,, and Sioud, M. (2009) Dendritic cells loaded with tumour antigens and a dual immunostimulatory and anti-interleukin-10-specific small interference RNA prime T lymphocyte against leukemic cells. Transl Oncol, 4, 242–246.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Immunology, Institute for Cancer Research, Rikshospitalet-Radiumhospitalet, University Hospital, Oslo, Norway

    Mouldy Sioud

Authors
  1. Mouldy Sioud
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Institute for Cancer Research, Dept. Immunology, Norwegian Radium Hospital, Montebello, Oslo, 0310, Norway

    Mouldy Sioud

Rights and permissions

Reprints and permissions

Copyright information

© 2010 Springer Science+Business Media, LLC

About this protocol

Cite this protocol

Sioud, M. (2010). Overcoming Self-Tolerance to Tumour Cells. In: Sioud, M. (eds) RNA Therapeutics. Methods in Molecular Biology, vol 629. Humana Press. https://doi.org/10.1007/978-1-60761-657-3_29

Download citation

  • DOI: https://doi.org/10.1007/978-1-60761-657-3_29

  • Published:

  • Publisher Name: Humana Press

  • Print ISBN: 978-1-60761-656-6

  • Online ISBN: 978-1-60761-657-3

  • eBook Packages: Springer Protocols

Publish with us

Policies and ethics

Search

Navigation