Skip to main content

Advertisement

SpringerLink
Log in

Intraperitoneal administration of poly(I:C) with polyethylenimine leads to significant antitumor immunity against murine ovarian tumors

  • Original article
  • Published:
Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

Abstract

Ovarian cancer is currently the most lethal gynecologic cancer in the United States. There is an urgent need for the development of innovative therapies against ovarian cancer, such as immunotherapy. The toll-like receptor 3 ligand, polyriboinosinic:polyribocytidylic acid (poly(I:C), has emerged as a promising adjuvant for activating the host immune responses for the control of tumors. We reasoned that a strategy to enhance the intracellular uptake of poly(I:C) will likely improve the poly(I:C) adjuvant effect. Since polyethylenimine (PEI) has been shown to increase the transfection efficiency of nucleic acids, we characterized the antitumor effects in mouse ovarian surface epithelial cells (MOSEC) tumor-bearing mice treated intraperitoneally with poly(I:C) and PEI. We observed that tumor-bearing mice treated with poly(I:C) and PEI generated significantly better therapeutic antitumor effects against MOSEC tumors compared with treatment with poly(I:C) alone. Furthermore, we found that NK cells play a significant role in the antitumor effects generated by treatment with poly(I:C) in combination with PEI. Intraperitoneal administration of poly(I:C) with PEI led to the uptake of poly(I:C) mainly by CD11b+ macrophages, resulting in the high expression of MHC class II and IL-12 (M1 phenotype). In addition, adoptive transfer of CD11b+ macrophages from mice treated with poly(I:C) and PEI was found to lead to increased number of activated NK cells in the recipient mice. Taken together, our data indicate that PEI can potentially be used to improve the uptake of poly(I:C) by CD11b+ macrophages, leading to the activation of NK cells and the control of murine ovarian tumors.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Aderem A, Ulevitch RJ (2000) Toll-like receptors in the induction of the innate immune response. Nature 406:782–787

    Article  PubMed  CAS  Google Scholar 

  2. Akira S (2001) Toll-like receptors and innate immunity. Adv Immunol 78:1–56

    Article  PubMed  CAS  Google Scholar 

  3. Akira S, Takeda K (2004) Toll-like receptor signalling. Nat Rev Immunol 4:499–511

    Article  PubMed  CAS  Google Scholar 

  4. Anwer K, Barnes MN, Fewell J, Lewis DH, Alvarez RD (2010) Phase-I clinical trial of IL-12 plasmid/lipopolymer complexes for the treatment of recurrent ovarian cancer. Gene Ther 17:360–369

    Article  PubMed  CAS  Google Scholar 

  5. Chan SH, Perussia B, Gupta JW, Kobayashi M, Pospisil M, Young HA et al (1991) Induction of interferon gamma production by natural killer cell stimulatory factor: characterization of the responder cells and synergy with other inducers. J Exp Med 173:869–879

    Article  PubMed  CAS  Google Scholar 

  6. Chuang CM, Monie A, Wu A, Mao CP, Hung CF (2009) Treatment with LL-37 peptide enhances antitumor effects induced by CpG oligodeoxynucleotides against ovarian cancer. Hum Gene Ther 20:303–313

    Article  PubMed  CAS  Google Scholar 

  7. Cubillos-Ruiz JR, Engle X, Scarlett UK, Martinez D, Barber A, Elgueta R et al (2009) Polyethylenimine-based siRNA nanocomplexes reprogram tumor-associated dendritic cells via TLR5 to elicit therapeutic antitumor immunity. J Clin Invest 119:2231–2244

    PubMed  CAS  Google Scholar 

  8. D’Andrea A, Rengaraju M, Valiante NM, Chehimi J, Kubin M, Aste M et al (1992) Production of natural killer cell stimulatory factor (interleukin 12) by peripheral blood mononuclear cells. J Exp Med 176:1387–1398

    Article  PubMed  Google Scholar 

  9. Fong CH, Bebien M, Didierlaurent A, Nebauer R, Hussell T, Broide D et al (2008) An antiinflammatory role for IKKbeta through the inhibition of “classical” macrophage activation. J Exp Med 205:1269–1276

    Article  PubMed  CAS  Google Scholar 

  10. Gordon S (2003) Alternative activation of macrophages. Nat Rev Immunol 3:23–35

    Article  PubMed  CAS  Google Scholar 

  11. Gordon S, Taylor PR (2005) Monocyte and macrophage heterogeneity. Nat Rev Immunol 5:953–964

    Article  PubMed  CAS  Google Scholar 

  12. Guermonprez P, Valladeau J, Zitvogel L, Thery C, Amigorena S (2002) Antigen presentation and T cell stimulation by dendritic cells. Annu Rev Immunol 20:621–667

    Article  PubMed  CAS  Google Scholar 

  13. Hagemann T, Lawrence T, McNeish I, Charles KA, Kulbe H, Thompson RG et al (2008) “Re-educating” tumor-associated macrophages by targeting NF-kappaB. J Exp Med 205:1261–1268

    Article  PubMed  CAS  Google Scholar 

  14. Hung CF, Tsai YC, He L, Wu TC (2007) Control of mesothelin-expressing ovarian cancer using adoptive transfer of mesothelin peptide-specific CD8+ T cells. Gene Ther 14:921–929

    Article  PubMed  CAS  Google Scholar 

  15. Iwasaki A, Medzhitov R (2004) Toll-like receptor control of the adaptive immune responses. Nat Immunol 5:987–995

    Article  PubMed  CAS  Google Scholar 

  16. Jemal A, Siegel R, Ward E, Murray T, Xu J, Thun MJ (2007) Cancer statistics, 2007. CA Cancer J Clin 57:43–66

    Article  PubMed  Google Scholar 

  17. Jiang Q, Wei H, Tian Z (2008) IFN-producing killer dendritic cells contribute to the inhibitory effect of poly I:C on the progression of murine melanoma. J Immunother 31:555–562

    Article  PubMed  CAS  Google Scholar 

  18. Kakimoto S, Hamada T, Komatsu Y, Takagi M, Tanabe T, Azuma H et al (2009) The conjugation of diphtheria toxin T domain to poly(ethylenimine) based vectors for enhanced endosomal escape during gene transfection. Biomaterials 30:402–408

    Article  PubMed  CAS  Google Scholar 

  19. Kobayashi M, Fitz L, Ryan M, Hewick RM, Clark SC, Chan S et al (1989) Identification and purification of natural killer cell stimulatory factor (NKSF), a cytokine with multiple biologic effects on human lymphocytes. J Exp Med 170:827–845

    Article  PubMed  CAS  Google Scholar 

  20. Lin K-Y, Guarnieri FG, Staveley-O’Carroll KF, Levitsky HI, August T, Pardoll DM et al (1996) Treatment of established tumors with a novel vaccine that enhances major histocompatibility class II presentation of tumor antigen. Cancer Res 56:21–26

    PubMed  CAS  Google Scholar 

  21. Martinez FO, Sica A, Mantovani A, Locati M (2008) Macrophage activation and polarization. Front Biosci 13:453–461

    Article  PubMed  CAS  Google Scholar 

  22. Matsumoto M, Seya T (2008) TLR3: interferon induction by double-stranded RNA including poly(I:C). Adv Drug Deliv Rev 60:805–812

    Article  PubMed  CAS  Google Scholar 

  23. Noel W, Raes G, Hassanzadeh Ghassabeh G, De Baetselier P, Beschin A (2004) Alternatively activated macrophages during parasite infections. Trends Parasitol 20:126–133

    Article  PubMed  CAS  Google Scholar 

  24. Robinson RA, DeVita VT, Levy HB, Baron S, Hubbard SP, Levine AS (1976) A phase I-II trial of multiple-dose polyriboinosic-polyribocytidylic acid in patients with leukemia or solid tumors. J Natl Cancer Inst 57:599–602

    PubMed  CAS  Google Scholar 

  25. Roby KF, Taylor CC, Sweetwood JP, Cheng Y, Pace JL, Tawfik O et al (2000) Development of a syngeneic mouse model for events related to ovarian cancer. Carcinogenesis 21:585–591

    Article  PubMed  CAS  Google Scholar 

  26. Salazar AM, Levy HB, Ondra S, Kende M, Scherokman B, Brown D et al. (1996) Long-term treatment of malignant gliomas with intramuscularly administered polyinosinic-polycytidylic acid stabilized with polylysine and carboxymethylcellulose: an open pilot study. Neurosurgery 38:1096–1104; discussion 1103–1104

    Google Scholar 

  27. Tripp CS, Wolf SF, Unanue ER (1993) Interleukin 12 and tumor necrosis factor alpha are costimulators of interferon gamma production by natural killer cells in severe combined immunodeficiency mice with listeriosis, and interleukin 10 is a physiologic antagonist. Proc Natl Acad Sci USA 90:3725–3729

    Article  PubMed  CAS  Google Scholar 

  28. Yoshihara C, Ito T, Shew CY, Koyama Y (2008) Improvement of transcription- and transfection-efficiency by synthetic polyampholytes. Nucleic Acids Symp Ser (Oxf) 52:713–714

    Article  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by the American Cancer Society (C.F. Hung).

Author information

Authors and Affiliations

  1. Department of Pathology, Johns Hopkins Medical Institutions, CRB II Room 307, 1550 Orleans Street, Baltimore, MD, 21231, USA

    Chao-Yi Wu, Archana Monie, Barbara Ma, T.-C. Wu & Chien-Fu Hung

  2. Department of Obstetrics and Gynecology, Johns Hopkins Medical Institutions, Baltimore, MD, USA

    T.-C. Wu

  3. Department of Molecular Microbiology and Immunology, Johns Hopkins Medical Institutions, Baltimore, MD, USA

    T.-C. Wu

  4. Department of Oncology, Johns Hopkins Medical Institutions, Baltimore, MD, USA

    T.-C. Wu & Chien-Fu Hung

  5. Department of Immunology, Johns Hopkins Medical Institutions, Baltimore, MD, USA

    Huang-Yu Yang

  6. Chang-Gung Memorial Hospital, Taipei, Taiwan

    Huang-Yu Yang

  7. Chang Gung University College of Medicine, Taipei, Taiwan

    Huang-Yu Yang

  8. Cathay General Hospital, Taipei, Taiwan

    Hsiao-Hsuan Tsai

Authors
  1. Chao-Yi Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Huang-Yu Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Archana Monie
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Barbara Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hsiao-Hsuan Tsai
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. T.-C. Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Chien-Fu Hung
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Chien-Fu Hung.

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wu, CY., Yang, HY., Monie, A. et al. Intraperitoneal administration of poly(I:C) with polyethylenimine leads to significant antitumor immunity against murine ovarian tumors. Cancer Immunol Immunother 60, 1085–1096 (2011). https://doi.org/10.1007/s00262-011-1013-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00262-011-1013-7

Keywords

Search

Navigation