Skip to main content

Advertisement

SpringerLink
Log in

Tumor sensitivity to IFN-γ is required for successful antigen-specific immunotherapy of a transplantable mouse tumor model for HPV-transformed tumors

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

Abstract

Purpose: Many human tumors lose responsiveness to IFN-γ, providing a possible mechanism for the tumor to avoid immune recognition and destruction. Here we investigate the importance of tumor responsiveness to IFN-γ in the successful immunotherapy of TC1 tumors that were immortalized with human papillomavirus proteins E6 and E7. Methods: To investigate the role of IFN-γ in vivo, we constructed a variant of TC1, TC1.mugR, that is unresponsive to IFN-γ due to overexpression of a dominant negative IFN-γ receptor. Results: Using recombinant Listeria monocytogenes that express HPV-16 E7 (Lm-LLO-E7) to stimulate an antitumor response, we demonstrate that sensitivity to IFN-γ is required for therapeutic efficacy in that Lm-LLO-E7 induces regression of TC1 tumors but not TC1.mugR. In addition, we show that tumor sensitivity to IFN-γ is not required for inhibition of tumor angiogenesis by Lm-LLO-E7 or for trafficking of CD4+ and CD8+ T cells to the tumor. However, it is required for penetration of lymphocytes into the tumor mass in vivo. Conclusions: Our findings identify a role for IFN-γ in immunity to TC1 tumors and show that loss of tumor responsiveness to IFN-γ poses a challenge to antigen-based immunotherapy.

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
Fig. 7
Fig. 8

Similar content being viewed by others

Abbreviations

BHI:

Brain heart infusion

CMV:

Cytomegalovirus

CTL:

Cytotoxic T lymphocyte

Hb:

Hemoglobin

HPV:

Human papillomavirus

IFN-γ:

Interferon-gamma

IL-12:

Interleukin-12

LLO:

Listeriolysin O

Lm:

Listeria monocytogenes

MHC:

Major histocompatibility class

MME:

Metalloelastase

NK:

Natural killer

PBS:

Phosphate-buffered saline

References

  1. Bosch FX, Manos MM, Munoz N, Sherman M, Jansen AM, Peto J, Schiffman MH, Moreno V, Kurman R, Shah KV (1995) Prevalence of human papillomavirus in cervical cancer: a worldwide perspective. International Biological Study on Cervical Cancer (IBSCC) study group. J Natl Cancer Inst 87:796

    Article  CAS  PubMed  Google Scholar 

  2. Mansur CP, Androphy EJ (1993) Cellular transformation by papillomavirus oncoproteins. Biochim Biophys Acta 1155:323

    Article  CAS  PubMed  Google Scholar 

  3. Wu TC (1994) Immunology of the human papilloma virus in relation to cancer. Curr Opin Immunol 6:746

    Article  CAS  PubMed  Google Scholar 

  4. Lin KY, Guarnieri FG, Staveley-O’Carroll KF, Levitsky HI, August JT, Pardoll DM, Wu TC (1996) Treatment of established tumors with a novel vaccine that enhances major histocompatibility class II presentation of tumor antigen. Cancer Res 56:21

    Google Scholar 

  5. Ji H, Chang EY, Lin KY, Kurman RJ, Pardoll DM, Wu TC (1998) Antigen-specific immunotherapy for murine lung metastatic tumors expressing human papillomavirus type 16 E7 oncoprotein. Int J Cancer 78:41

    Google Scholar 

  6. Gunn GR, Zubair A, Peters C, Pan ZK, Wu TC, Paterson Y (2001) Two Listeria monocytogenes vaccine vectors that express different molecular forms of human papilloma virus-16 (HPV-16) E7 induce qualitatively different T cell immunity that correlates with their ability to induce regression of established tumors immortalized by HPV-16. J Immunol 167:6471

    CAS  PubMed  Google Scholar 

  7. Pan ZK, Ikonomidis G, Pardoll D, Paterson Y (1995) Regression of established tumors in mice mediated by the oral administration of a recombinant Listeria monocytogenes vaccine. Cancer Res 55:4776

    Google Scholar 

  8. Pan ZK, Ikonomidis G, Lazenby A, Pardoll D, Paterson Y (1995) A recombinant Listeria monocytogenes vaccine expressing a model tumour antigen protects mice against lethal tumour cell challenge and causes regression of established tumours. Nat Med 1:471

    Article  CAS  PubMed  Google Scholar 

  9. Pan ZK, Weiskirch LM, Paterson Y (1999) Regression of established B16F10 melanoma with a recombinant Listeria monocytogenes vaccine. Cancer Res 59:5264

    Google Scholar 

  10. Woodworth CD, Lichti U, Simpson S, Evans CH, DiPaolo JA (1992) Leukoregulin and gamma-interferon inhibit human papillomavirus type 16 gene transcription in human papillomavirus-immortalized human cervical cells. Cancer Res 52:456

    Google Scholar 

  11. Kim KY, Blatt L, Taylor MW (2000) The effects of interferon on the expression of human papillomavirus oncogenes. J Gen Virol 81:695

    CAS  PubMed  Google Scholar 

  12. Tartour E, Gey A, Sastre-Garau X, Lombard Surin I, Mosseri V, Fridman WH (1998) Prognostic value of intratumoral interferon gamma messenger RNA expression in invasive cervical carcinomas. J Natl Cancer Inst 90:287

    Article  CAS  PubMed  Google Scholar 

  13. Dunn GP, Bruce AT, Ikeda H, Old LJ, Schreiber RD (2002) Cancer immunoediting: from immunosurveillance to tumor escape. Nat Immunol 3:991

    Article  CAS  PubMed  Google Scholar 

  14. Feltkamp MC, Smits HL, Vierboom MP, Minnaar RP, de Jongh BM, Drijfhout JW, ter Schegget J, Melief CJ, Kast WM (1993) Vaccination with cytotoxic T lymphocyte epitope-containing peptide protects against a tumor induced by human papillomavirus type 16-transformed cells. Eur J Immunol 23:2242

    CAS  PubMed  Google Scholar 

  15. Mata M, Yao ZJ, Zubair A, Syres K, Paterson Y (2001) Evaluation of a recombinant Listeria monocytogenes expressing an HIV protein that protects mice against viral challenge. Vaccine 19:1435

    Article  CAS  PubMed  Google Scholar 

  16. Kleinman HK, McGarvey ML, Liotta LA, Robey PG, Tryggvason K, Martin GR (1982) Isolation and characterization of type IV procollagen, laminin, and heparan sulfate proteoglycan from the EHS sarcoma. Biochemistry 21:6188

    CAS  PubMed  Google Scholar 

  17. Passaniti A, Taylor RM, Pili R, Guo Y, Long PV, Haney JA, Pauly RR, Grant DS, Martin GR (1992) A simple, quantitative method for assessing angiogenesis and antiangiogenic agents using reconstituted basement membrane, heparin, and fibroblast growth factor. Lab Invest 67:519

    CAS  PubMed  Google Scholar 

  18. Winn HJ (1972) In vivo methods for the assessment of antibody-mediate tumor immunity. J Natl Cancer Inst Monogr 35:13

    CAS  Google Scholar 

  19. Dighe AS, Richards E, Old LJ, Schreiber RD (1994) Enhanced in vivo growth and resistance to rejection of tumor cells expressing dominant negative IFN gamma receptors. Immunity 1:447

    Article  CAS  PubMed  Google Scholar 

  20. Beatty GL, Paterson Y (2000) IFN-gamma can promote tumor evasion of the immune system in vivo by down-regulating cellular levels of an endogenous tumor antigen. J Immunol 165:5502

    CAS  PubMed  Google Scholar 

  21. Sgadari C, Angiolillo AL, Tosato G (1996) Inhibition of angiogenesis by interleukin-12 is mediated by the interferon-inducible protein 10. Blood 87:3877

    CAS  PubMed  Google Scholar 

  22. Majewski S, Marczak M, Szmurlo A, Jablonska S, Bollag W (1996) Interleukin-12 inhibits angiogenesis induced by human tumor cell lines in vivo. J Invest Dermatol 106:1114

    Article  CAS  PubMed  Google Scholar 

  23. Voest EE, Kenyon BM, O’Reilly MS, Truitt G, D’Amato RJ, Folkman J (1995) Inhibition of angiogenesis in vivo by interleukin 12. J Natl Cancer Inst 87:581

    CAS  PubMed  Google Scholar 

  24. Coughlin CM, Salhany KE, Gee MS, LaTemple DC, Kotenko S, Ma X, Gri G, Wysocka M, Kim JE, Liu L, Liao F, Farber JM, Pestka S, Trinchieri G, Lee WM (1998) Tumor cell responses to IFN-gamma affect tumorigenicity and response to IL-12 therapy and antiangiogenesis. Immunity 9:25

    Article  CAS  PubMed  Google Scholar 

  25. Peng X, Hussain SF, Paterson Y (2004) The ability of two Listeria monocytogenes vaccines targeting human papillomavirus-16 E7 to induce an antitumor response correlates with myeloid dendritic cell function. J Immunol 172:6030

    CAS  PubMed  Google Scholar 

  26. Ogawa M, Tsutsui T, Zou JP, Mu J, Wijesuriya R, Yu WG, Herrmann S, Kubo T, Fujiwara H, Hamaoka T (1997) Enhanced induction of very late antigen 4/lymphocyte function-associated antigen 1-dependent T-cell migration to tumor sites following administration of interleukin 12. Cancer Res 57:2216

    Google Scholar 

  27. Ogawa M, Yu WG, Umehara K, Iwasaki M, Wijesuriya R, Tsujimura T, Kubo T, Fujiwara H, Hamaoka T (1998) Multiple roles of interferon-gamma in the mediation of interleukin 12-induced tumor regression. Cancer Res 58:2426

    Google Scholar 

  28. Min W, Pober JS, Johnson DR (1996) Kinetically coordinated induction of TAP1 and HLA class I by IFN-gamma: the rapid induction of TAP1 by IFN-gamma is mediated by Stat1 alpha. J Immunol 156:3174

    CAS  PubMed  Google Scholar 

  29. Seliger B, Wollscheid U, Momburg F, Blankenstein T, Huber C (2000) Coordinate downregulation of multiple MHC class I antigen processing genes in chemical-induced murine tumor cell lines of distinct origin. Tissue Antigens 56:327

    Article  CAS  PubMed  Google Scholar 

  30. Smahel M, Sima P, Ludvikova V, Marinov I, Pokorna D, Vonka V (2003) Immunisation with modified HPV16 E7 genes against mouse oncogenic TC1 cell sublines with downregulated expression of MHC class I molecules. Vaccine 21:1125

    Article  CAS  PubMed  Google Scholar 

  31. Wang Z, Margulies L, Hicklin DJ, Ferrone S (1996) Molecular and functional phenotypes of melanoma cells with abnormalities in HLA class I antigen expression. Tissue Antigens 47:382

    CAS  PubMed  Google Scholar 

  32. Chatterjee-Kishore M, Kishore R, Hicklin DJ, Marincola FM, Ferrone S (1998) Different requirements for signal transducer and activator of transcription 1alpha and interferon regulatory factor 1 in the regulation of low molecular mass polypeptide 2 and transporter associated with antigen processing 1 gene expression. J Biol Chem 273:16177

    Article  CAS  PubMed  Google Scholar 

  33. Beatty G, Paterson Y (2001) IFN-gamma-dependent inhibition of tumor angiogenesis by tumor-infiltrating CD4+ T cells requires tumor responsiveness to IFN-gamma. J Immunol 166:2276

    CAS  PubMed  Google Scholar 

  34. Qin Z, Blankenstein T (2000) CD4+ T cell–mediated tumor rejection involves inhibition of angiogenesis that is dependent on IFN gamma receptor expression by nonhematopoietic cells. Immunity 12:677

    Article  CAS  PubMed  Google Scholar 

  35. Harty JT, Schreiber RD, Bevan MJ (1992) CD8 T cells can protect against an intracellular bacterium in an interferon gamma-independent fashion. Proc Natl Acad Sci U S A 89:11612

    CAS  PubMed  Google Scholar 

  36. Harty JT, Bevan MJ (1995) Specific immunity to Listeria monocytogenes in the absence of IFN-gamma. Immunity 3:109

    Article  CAS  PubMed  Google Scholar 

  37. Badovinac VP, Harty JT (2000) Adaptive immunity and enhanced CD8+ T cell response to Listeria monocytogenes in the absence of perforin and IFN-gamma. J Immunol 164:6444

    CAS  PubMed  Google Scholar 

  38. Bukowski RM, Rayman P, Molto L, Tannenbaum CS, Olencki T, Peereboom D, Tubbs R, McLain D, Budd GT, Griffin T, Novick A, Hamilton TA, Finke J (1999) Interferon-gamma and CXC chemokine induction by interleukin 12 in renal cell carcinoma. Clin Cancer Res 5:2780

    CAS  PubMed  Google Scholar 

  39. Kunz M, Toksoy A, Goebeler M, Engelhardt E, Brocker E, Gillitzer R (1999) Strong expression of the lymphoattractant C-X-C chemokine Mig is associated with heavy infiltration of T cells in human malignant melanoma. J Pathol 189:552

    Article  CAS  PubMed  Google Scholar 

  40. Tannenbaum CS, Tubbs R, Armstrong D, Finke JH, Bukowski RM, Hamilton TA (1998) The CXC chemokines IP-10 and Mig are necessary for IL-12-mediated regression of the mouse RENCA tumor. J Immunol 161:927

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by NIH grant CA69632 and ACS grant TURSG LIB-101399 (Y.P.), and NIH training grant T32CA09140 (G.L.B). We would like to thank Dr S. Farzana Hussain for critically reading this manuscript.

Author information

Authors and Affiliations

  1. Department of Microbiology, University of Pennsylvania, 323 Johnson Pavilion, 3610 Hamilton Walk, Philadelphia, PA, 19104-6076, USA

    Mary E. Dominiecki, Gregory L. Beatty, Zhen-Kun Pan, Paul Neeson & Yvonne Paterson

Authors
  1. Mary E. Dominiecki
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Gregory L. Beatty
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Zhen-Kun Pan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Paul Neeson
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yvonne Paterson
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yvonne Paterson.

Additional information

Mary E. Dominiecki and Gregory L. Beatty contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Dominiecki, M.E., Beatty, G.L., Pan, ZK. et al. Tumor sensitivity to IFN-γ is required for successful antigen-specific immunotherapy of a transplantable mouse tumor model for HPV-transformed tumors. Cancer Immunol Immunother 54, 477–488 (2005). https://doi.org/10.1007/s00262-004-0610-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00262-004-0610-0

Keywords

Search

Navigation