Class C CpG oligodeoxynucleotides as a single agent and in combination with radiotherapy efficiently delayed growth of subcutaneous B16F1 tumors

Abstract

Until now, the anti-tumor efficacy of synthetic oligodeoxynucleotides containing CpG motifs (CpG ODNs) has been reported in a number of preventive and therapeutic tumor models. Predominately class B CpG ODNs were used, relatively little has been reported regarding the class C CpG ODNs. The present study was, therefore, aimed at assessing the ability of CpG ODNs class C applied as a single agent and in combination with radiotherapy to induce the anti-tumor immunity in an experimental tumor model in mice (subcutaneous [s.c.] B16F1). Class C CpG ODNs applied three times as a single agent efficiently delayed the growth of s.c. B16F1 tumors. The combined therapy (CpG ODNs and tumor irradiation) remarkably enhanced the anti-tumor effect. The peritumoral (p.t.) application of CpG ODNs in combination with irradiation increased the number of dendritic cells (DCs) at the tumor site and improved the antigen loading and maturation of DCs. In conclusion, the combined therapy with CpG ODNs and irradiation creates a unique in situ DCs vaccine that could be easily applicable without prior knowledge of tumor antigens.

Keywords

CpG ODN dendritic cells innate immunity radiotherapy tumor vaccine

References

Furumoto K. , Soares L. , Engleman EG , Merad M. Induction of potent antitumor immunity by in situ targeting of intratumoral DCs. J Clin Invest 2004; 113: 774-783.

Bui JD , Schreiber RD

Cancer immunosurveillance, immunoediting and inflammation: independent or interdependent processes?

Curr Opin Immunol 2007; 19: 203-208.

Pinzon-Charry A. , Maxwell T. , Lopez JA Dendritic cell dysfunction in cancer: a mechanism for immunosuppression. Immunol Cell Biol 2005 ; 83: 451-461.

Novakovic S. , Stegel V. , Kopitar A. , Ihan A. , Novakovic BJ Preventive and therapeutic effect of tumor vaccine composed of CpG ODN class C and irradiated tumor cells is triggered through the APCs and activation of CTLs. Vaccine 2007; 25: 8241-8256.

Malmberg KJ , Ljunggren HG Escape from immune- and nonimmune-mediated tumor surveillance. Semin Cancer Biol 2006 ; 16: 16-31.

Krieg AM Therapeutic potential of Toll-like receptor 9 activation. Nat Rev Drug Discov 2006; 5: 471-484.

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: 539-547.

Jahrsdorfer B. , Weiner GJ CpG oligodeoxynucletides as immunotherapy in cancer. Update Cancer Ther 2008; 3: 27-32.

Brown L. , Roda BS , Terrell C. et al. Interferon α and CpG oligodeoxynucleotides elicit additive immunostimulatory and antitumor effects. Surgery 2006; 140: 297-306.

10.

Kaisho T. , Akira S. Toll-like receptor function and signaling. J Allergy Clin Immunol 2006; 117: 979-987.

11.

Pilon-Thomas S. , Li W. , Briggs JJ , Djeu J. , Mule JJ , Riker AI Immunostimulatory effects of CpG-ODN upon dendritic cell-based immunotherapy in murine melanoma model. J Immunother 2006; 29: 381-387.

12.

Friedberg JW , Kim H. , McCauley M. et al. Combination immunotherapy with CpG oligonucleotide (1018 ISS) and rituximab in patients with non-Hodgkin lymphoma: increased interferon-α/β-inducible gene expression, without significant toxicity. Blood 2005; 105: 489-495.

13.

Weeratna RD , Davis HL , Medynski L. , Krieg AM Potential use of CpG ODN for cancer immunotherapy . Update Cancer Ther 2006; 1: 49-58.

14.

Stegel V. , Kopitar A. , Jezersek NB , Ihan A. , Novakovic S. Dendritic cells incubated with irradiated tumor cells effectively stimulate T lymphocyte activation and induce enhanced expression of CD69, CD25 as well as production of IFNγ and IL4. Int Immunopharmacol 2006; 6: 79-89.

15.

den Brok Mhmgm , Sutmuller RPM , Nierkens S. et al. Synergy between in situ cryoablation and TLR9 stimulation results in a highly effective in vivo dendritic cell vaccine. Cancer Res 2006; 66: 7285-7292.

16.

Lonsdorf AS , Kuekrek H. , Stern BV , Boehm BO , Lehmann PV , Tary-Lehmann M. Intratumor CpG-oligodeoxynucletide injection induces protective antitumor T cell immunity . J Immunol 2003; 171: 3941-3946.

17.

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: 3235-3245.

18.

Switaj T. , Jalili A. , Jakubowska AB et al. CpG immunostimulatory oligodeoxynucletide 1826 enhances antitumor effect of interleukin 12 gene-modified tumor vaccine in a melanoma model in mice. Clin Cancer Res 2004; 10: 4165-4175.

19.

Mason KA , Neal R. , Hunter N. , Ariga H. , Ang K. , Milas L. CpG oligodeoxynucleotides are potent enhancers of radio- and chemoresponses of murine tumors. Radiother Oncol 2006; 80: 192-198.

20.

Mason KA , Ariga H. , Neal R. et al. Targeting Toll-like receptor 9 with CpG oligodeoxynucleotides enhances tumor response to fractionated radiotherapy. Clin Cancer Res 2005; 11: 361-369.

21.

Milas L. , Mason KA , Ariga H. et al. CpG oligodeoxynucleotides enhances tumor response to radiation . Cancer Res 2004; 64: 5074-5077.

22.

Meng Y. , Carpentier AF , Chen L. et al. Successful combination of local CpG ODN and radiotherapy in malignant glioma. Int J Cancer 2005; 116: 992-997.

23.

Speiser DE , Lienard D. , Rufer N. et al. Rapid and strong human CD8+ T cell responses to vaccination with peptide, IFA and CpG oligodeoxynucletide 7909. J Clin Invest 2005; 115: 739-746.

24.

Saha A. , Baral RN , Chatterjee SK et al. CpG oligonucleotides enhance the tumor antigen-specific immune response of an antiidiotype antibody-based vaccine strategy in CEA transgenic mice. Cancer Immunol Immunother 2006; 55: 515-527.

25.

Carpentier A. , Laigle-Donadey F. , Zohar S. et al. Phase 1 trial of a CpG oligodeoxynucleotide for patients with recurrent glioblastoma. Neurol Oncol 2006; 8: 60-66.

26.

Ohashi K. , Kobayashi G. , Fang S. et al. Surgical excision combined with autologous whole tumor cell vaccination is an effective therapy for murine neuroblastoma. J Pediatr Surg 2006; 41: 1361-1368.

27.

Spector SA , Tyndall M. , Kelley E. Effects of acyclovir combined with other antiviral agents on human cytomegalovirus . Am J Med 1982; 73: 36-39.

28.

Merad M. , Sugie T. , Engleman EG , Fong L. In vivo manipulation of dendritic cells to induce therapeutic immunity . Blood 2002; 99: 1676-1682.

29.

Buhtoiarov IN , Sondel PM , Eickhoff JC , Rakhmilevich AL Macrophages are essential for antitumour effects against weakly immunogenic murine tumours induced by class B CpG-oligodeoxynucleotides . Immunology 2006; 120: 412-423.

30.

Zhu B. , Zou L. , Cheng X. et al. Administration of MIP-3α gene to the tumor following radiation therapy boosts anti-tumor immunity in a murine model of lung carcinoma. Immunol Lett 2006; 103: 101-107.