Abstracts
Résumé
La mise en évidence de séquences immunostimulantes au sein des brins d’ADN en dehors de toute traduction est une découverte récente de la biologie de l’ADN. La présence de motifs CpG, reconnus par un récepteur spécifique (Toll-like receptor 9), induit l’activation des macrophages, des cellules natural killer (NK) et des lymphocytes B, et oriente la réponse lymphocytaire T vers le profil Th1. Les propriétés immunostimulantes des motifs CpG ont été utilisées avec succès dans de nombreux modèles animaux de vaccins, d’allergies ou de maladies infectieuses, et plusieurs essais cliniques sont en cours. Dans le cas des cancers, lorsqu’un antigène tumoral est connu, les motifs CpG peuvent être utilisés comme adjuvants dans un cadre vaccinal, ou combinés avec des anticorps monoclonaux. Dans les autres cas, des oligonucléotides de synthèse portant des motifs CpG (CpG-ODN) peuvent être utilisés de façon locale pour stimuler l’immunité innée et favoriser l’émergence d’une réponse immune spécifique. Cet article fait le point sur les progrès récents dans l’utilisation des CpG-ODN en cancérologie.
Summary
Bacterial DNA and synthetic oligodeoxynucléotides containing CpG motifs (CpG-ODN) are the ligands for the Toll-like receptor 9 (TLR9), which is expressed by B-lymphocytes and a subset of dendritic cells. CpG-ODN are strong activators of both innate and specific immunity, and drive the immune response towards the Th1 phenotype. Given the promising results obtained in several experimental models of allergies or infections, CpG-ODN are now entering clinical trials for these diseases. In cancer, promising approaches combined CpG-ODN with tumor antigens, monoclonal antibodies or dendritic cells. When no relevant tumor antigen is known, CpG-ODN can be used alone to activate locally the innate immunity and trigger a tumor-specific immune response, overcoming the need for the identification of a tumoral antigen. Preclinical models have shown impressive results and several clinical trials are on-going worldwide in melanoma, lymphoma, renal carcinoma, breast cancer and glioblastoma.
Appendices
Références
- 1. Tokunaga T, Yamamoto H, Shimada S, et al. Antitumor activity of deoxyribonucleic acid fraction from Mycobacterium bovis BCG. I. Isolation, physicochemical characterization, and antitumor activity. J Natl Cancer Inst 1984 ; 72 : 955-62.
- 2. Krieg AM, Yi AK, Matson S, et al. CpG motifs in bacterial DNA trigger direct B-cell activation. Nature 1995 ; 374 : 546-9.
- 3. Yamamoto S, Yamamoto T, Kataoka T, et al. Unique palindromic sequences in synthetic oligonucleotides are required to induce IFN and augment IFN-mediated natural killer activity. J Immunol 1992 ; 148 : 4072-6.
- 4. Hacker H. Signal transduction pathways activated by CpG-DNA. Curr Top Microbiol Immunol 2000 ; 247 : 77-92.
- 5. Hemmi H, Takeuchi O, Kawai T, et al. Toll-like receptor recognizes bacterial DNA. Nature 2000 ; 408 : 740-5.
- 6. Takeshita F, Leifer CA, Gursel I, et al. Cutting edge : role of Toll-like receptor 9 in CpG DNA-induced activation of human cells. J Immunol 2001 ; 167 : 3555-8.
- 7. Klinman DM. Immunotherapeutic uses of CpG oligodeoxynucleotides. Nat Rev Immunol 2004 ; 4 : 249-59.
- 8. Hornung V, Rothenfusser S, Britsch S, et al. Quantitative expression of toll-like receptor 1-10 mRNA in cellular subsets of human peripheral blood mononuclear cells and sensitivity to CpG oligodeoxynucleotides. J Immunol 2002 ; 168 : 4531-7.
- 9. Carpentier AF, Auf G, Delattre JY. CpG-oligonucleotides for cancer immunotherapy : review of the literature and potential applications in malignant glioma. Front Biosci 2003 ; 8 : E115-27.
- 10. Jung J, Yi AK, Zhang X, et al. Distinct response of human B cell subpopulations in recognition of an innate immune signal, CpG DNA. J Immunol 2002 ; 169 : 2368-73.
- 11. Sparwasser T, Koch ES, Vabulas RM, et al. Bacterial DNA and immunostimulatory CpG oligonucleotides trigger maturation and activation of murine dendritic cells. Eur J Immunol 1998 ; 28 : 2045-54.
- 12. Ban E, Dupre L, Hermann E, et al. CpG motifs induce Langerhans cell migration in vivo. Int Immunol 2000 ; 12 : 737-45.
- 13. Krug A, Towarowski A, Britsch S, et al. Toll-like receptor expression reveals CpG DNA as a unique microbial stimulus for plasmacytoid dendritic cells which synergizes with CD40 ligand to induce high amounts of IL-12. Eur J Immunol 2001 ; 31 : 3026-37.
- 14. Kline JN, Waldschmidt TJ, Businga TR, et al. Modulation of airway inflammation by CpG oligodeoxynucleotides in a murine model of asthma. J Immunol 1998 ; 160 : 2555-9.
- 15. Cho HJ, Takabayashi K, Cheng PM, et al. Immunostimulatory DNA-based vaccines induce cytotoxic lymphocyte activity by a T-helper cell-independent mechanism. Nat Biotechnol 2000 ; 18 : 509-14.
- 16. Krieg AM. Antitumor applications of stimulating toll-like receptor 9 with CpG oligodeoxynucleotides. Curr Oncol Rep 2004 ; 6 : 88-95.
- 17. Hartmann G, Weeratna RD, Ballas ZK, et al. Delineation of a CpG phosphorothioate oligodeoxynucleotide for activating primate immune responses in vitro and in vivo. J Immunol 2000 ; 164 : 1617-24.
- 18. Carpentier AF, Chen L, Maltonti F, Delattre JY. Oligodeoxynucleotides containing CpG motifs can induce rejection of a neuroblastoma in mice. Cancer Res 1999 ; 59 : 5429-32.
- 19. Carpentier AF, Xie J, Mokhtari K, Delattre JY. Successful treatment of intracranial gliomas in rat by oligodeoxynucleotides containing CpG motifs. Clin Cancer Res 2000 ; 6 : 2469-73.
- 20. Decker T, Schneller F, Sparwasser T, et al. Immunostimulatory CpG-oligonucleotides cause proliferation, cytokine production, and an immunogenic phenotype in chronic lymphocytic leukemia B cells. Blood 2000 ; 95 : 999-1006.
- 21. Hafner M, Zawatzky R, Hirtreiter C, et al. Antimetastatic effect of CpG DNA mediated by type I IFN. Cancer Res 2001 ; 61 : 5523-8.
- 22. Lanuti M, Rudginsky S, Force SD, et al. Cationic lipid/bacterial DNA complexes elicit adaptive cellular immunity in murine intraperitoneal tumor models. Cancer Res 2000 ; 60 : 2955-63.
- 23. Kawarada Y, Ganss R, Garbi N, et al. NK- and CD8+ T cell-mediated eradication of established tumors by peritumoral injection of CpG-containing oligodeoxynucleotides. J Immunol 2001 ; 167 : 5247-53
- 24. Hartmann E, Wollenberg B, Rothenfusser S, et al. Identification and functional analysis of tumor-infiltrating plasmacytoid dendritic cells in head and neck cancer. Cancer Res 2003 ; 63 : 6478-87.
- 25. Vicari AP, Chiodoni C, Vaure C, et al. Reversal of tumor-induced dendritic cell paralysis by CpG immunostimulatory oligonucleotide and anti-interleukin 10 receptor antibody. J Exp Med 2002 ; 196 : 541-9.
- 26. Trefzer U, Kors C, Pelzer K, et al. Preliminary results of a phase I trial of intralesional injection of CpG-DNA in basal cell carcinoma and melanoma. 2nd International Symposium Activating immunity with CpG Oligos. Amelia Island, Florida, 7-10 octobre 2001.
- 27. Krieg AM. CpG motifs in bacterial DNA and their immune effects. Annu Rev Immunol 2002 ; 20 : 709-60.
- 28. Zwaveling S, Ferreira Mota SC, Nouta J, et al. Established human papillomavirus type 16-expressing tumors are effectively eradicated following vaccination with long peptides. J Immunol 2002 ; 169 : 350-8.
- 29. Miconnet I, Koenig S, Speiser D, et al. CpG are efficient adjuvants for specific CTL induction against tumor antigen-derived peptide. J Immunol 2002 ; 68 : 1212-8.
- 30. Davila E , Celis E. Repeated administration of cytosine-phosphorothiolated guanine-containing oligonucleotides together with peptide/protein immunization results in enhanced CTL responses with anti-tumor activity. J Immunol 2000 ; 165 : 539-47.
- 31. Tighe H, Takabayashi K, Schwartz D, et al. Conjugation of immunostimulatory DNA to the short ragweed allergen amb a 1 enhances its immunogenicity and reduces its allergenicity. J Allergy Clin Immunol 2000 ; 106 : 124-34.
- 32. Kim SK, Ragupathi G, Cappello S, et al. Effect of immunological adjuvant combinations on the antibody and T-cell response to vaccination with MUC1-KLH and GD3-KLH conjugates. Vaccine 2000 ; 19 : 530-7.
- 33. Liu HM, Newbrough SE, Bhatia SK, et al. Immunostimulatory CpG oligodeoxynucleotides enhance the immune response to vaccine strategies involving granulocyte-macrophage colony-stimulating factor. Blood 1998 ; 92 : 3730-6.
- 34. Warren TL, Dahle CE, GJ Weiner. CpG oligodeoxynucleotides enhance monoclonal antibody therapy of a murine lymphoma. Clin Lymphoma 2000 ; 1 : 57-61.
- 35. Decker T, Hipp S, Kreitman RJ, et al. Sensitization of B-cell chronic lymphocytic leukemia cells to recombinant immunotoxin by immunostimulatory phosphorothioate oligodeoxynucleotides. Blood 2002 ; 99 : 1320-6.
- 36. Egeter OR, Mocikat K, Ghoreschi A, et al. Eradication of disseminated lymphomas with CpG-DNA activated T helper type 1 cells from nontransgenic mice. Cancer Res 2000 ; 60 : 1515-20.
- 37. Heckelsmiller K, Beck S, Rall K, et al. Combined dendritic cell and CpG oligonucleotide-based immune therapy cures large murine tumors that resist chemotherapy. Eur J Immunol 2002 ; 32 : 3235-45.
- 38. Weigel BJ, Rodeberg DA, Krieg AM, Blazar BR. CpG oligodeoxynucleotides potentiate the antitumor effects of chemotherapy or tumor resection in an orthotopic murine model of rhabdomyosarcoma. Clin Cancer Res 2003 ; 9 : 3105-14.