Skip to main content

Advertisement

SpringerLink
Log in

Small numbers of residual tumor cells at the site of primary inoculation are critical for anti-tumor immunity following challenge at a secondary location

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

Abstract

Luciferase-transduced B16 murine melanoma cells (luc-B16) inoculated in ear skin do not form tumors but prevent tumor formation by luc-B16 cells injected into the footpad. To determine the requirements for such immunity, we followed the fate of luc-B16 cells following ear injection. Surprisingly, small numbers of viable luc-B16 cells were detected in tumor-free mouse skin for up to 60 days post-inoculation. After 1 week, the number of Foxp3+CD4+CD25+ T cells (along with foxp3 mRNA expression) increased rapidly in the injected ear skin. Residual tumor cells in ears were reduced in mice treated with anti-CD25 mAb and in CD4-deficient mice, but increased in CD8-deficient mice. Strikingly, the loss of luc-B16 cells in the ear skin, either spontaneously or following amputation of the injected ear, resulted in significantly enhanced tumor formation by parental and luciferase-expressing B16 cells after footpad injection. These studies suggest that small numbers of tumor cells (possibly regulated by CD4+CD25+ regulatory T cells expressing Foxp3) are required for effective host anti-tumor responses at alternate inoculation sites.

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

Tregs:

Regulatory T cells

luc:

Luciferase

CTL:

Cytolytic T lymphocytes (cells)

References

  1. Antony PA, Restifo NP (2002) Do CD4+ CD25+ immunoregulatory T cells hinder tumor immunotherapy? J Immunother 25:202–206

    Article  PubMed  CAS  Google Scholar 

  2. Bashford E, Murray J, Haaland M (1908) Resistance and suceptibility to inoculated cancer. In: Bashford E (ed) Third scientific report on the investigations of the imperial cancer research fund. Taylor & Francis, London pp 359–397

    Google Scholar 

  3. Belkaid Y, Hoffmann KF, Mendez S, Kamhawi S, Udey MC, Wynn TA et al (2001) The role of interleukin (IL)-10 in the persistence of Leishmania major in the skin after healing and the therapeutic potential of anti-IL-10 receptor antibody for sterile cure. J Exp Med 194:1497–1506

    Article  PubMed  CAS  Google Scholar 

  4. Belkaid Y, Piccirillo CA, Mendez S, Shevach EM, Sacks DL (2002) CD4+CD25+ regulatory T cells control Leishmania major persistence and immunity. Nature 420:502–507

    Article  PubMed  CAS  Google Scholar 

  5. Butterfield LH, Ribas A, Dissette VB, Amarnani SN, Vu HT, Oseguera D et al (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 

  6. Coussens LM, Werb Z (2001) Inflammatory cells and cancer: think different! J Exp Med 193:F23–F26

    Article  PubMed  CAS  Google Scholar 

  7. Curiel TJ, Coukos G, Zou L, Alvarez X, Cheng P, Mottram P et al (2004) Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat Med 10:942–949

    Article  PubMed  CAS  Google Scholar 

  8. Dannull J, Su Z, Rizzieri D, Yang BK, Coleman D, Yancey D et al (2005) Enhancement of vaccine-mediated antitumor immunity in cancer patients after depletion of regulatory T cells. J Clin Invest 115:3623–3633

    Article  PubMed  CAS  Google Scholar 

  9. Dranoff G, Jaffee E, Lazenby A, Golumbek P, Levitsky H, Brose K et al (1993) Vaccination with irradiated tumor cells engineered to secrete murine granulocyte-macrophage colony-stimulating factor stimulates potent, specific, and long-lasting anti-tumor immunity. Proc Natl Acad Sci USA 90:3539–3543

    Article  PubMed  CAS  Google Scholar 

  10. Dudley ME, Wunderlich J, Nishimura MI, Yu D, Yang JC, Topalian SL, et al. (2001) Adoptive transfer of cloned melanoma-reactive T lymphocytes for the treatment of patients with metastatic melanoma. J Immunother 24:363–373

    Article  PubMed  CAS  Google Scholar 

  11. Ehrlich P (1906) Collected studies on immunity. Wiley, London

    Google Scholar 

  12. Fidler IJ (1973) Selection of successive tumour lines for metastasis. Nature (New Biol) 242:148–149

    CAS  Google Scholar 

  13. Fontenot JD, Rudensky AY (2005) A well adapted regulatory contrivance: regulatory T cell development and the forkhead family transcription factor Foxp3. Nat Immunol 6:331–337

    Article  PubMed  CAS  Google Scholar 

  14. Franco M, Bustuoabad OD, di Gianni PD, Goldman A, Pasqualini CD, Ruggiero RA (1996) A serum-mediated mechanism for concomitant resistance shared by immunogenic and non-immunogenic murine tumours. Br J Cancer 74:178–186

    PubMed  CAS  Google Scholar 

  15. Kobayashi H, Kawamoto S, Choyke PL, Sato N, Knopp MV, Star RA et al (2003) Comparison of dendrimer-based macromolecular contrast agents for dynamic micro-magnetic resonance lymphangiography. Magn Reson Med 50:758–766

    Article  PubMed  CAS  Google Scholar 

  16. Kobayashi H, Kawamoto S, Star RA, Waldmann TA, Tagaya Y, Brechbiel MW (2003) Micro-magnetic resonance lymphangiography in mice using a novel dendrimer-based magnetic resonance imaging contrast agent. Cancer Res 63:271–276

    PubMed  CAS  Google Scholar 

  17. Lee PP, Yee C, Savage PA, Fong L, Brockstedt D, Weber JS et al (1999) Characterization of circulating T cells specific for tumor-associated antigens in melanoma patients. Nat Med 5:677–685

    Article  PubMed  CAS  Google Scholar 

  18. Ljunggren HG, Karre K (1985) Host resistance directed selectively against H-2-deficient lymphoma variants. Analysis of the mechanism. J Exp Med 162:1745–1759

    Article  PubMed  CAS  Google Scholar 

  19. Murakami T, Cardones AR, Finkelstein SE, Restifo NP, Klaunberg BA, Nestle FO et al (2003) Immune evasion by murine melanoma mediated through CC chemokine receptor-10. J Exp Med 198:1337–1347

    Article  PubMed  CAS  Google Scholar 

  20. Nagai H, Horikawa T, Hara I, Fukunaga A, Oniki S, Oka M et al (2004) In vivo elimination of CD25+ regulatory T cells leads to tumor rejection of B16F10 melanoma, when combined with interleukin-12 gene transfer. Exp Dermatol 13:613–620

    Article  PubMed  CAS  Google Scholar 

  21. Ochsenbein AF, Sierro S, Odermatt B, Pericin M, Karrer U, Hermans J et al (2001) Roles of tumour localization, second signals and cross priming in cytotoxic T-cell induction. Nature 411:1058–1064

    Article  PubMed  CAS  Google Scholar 

  22. Onizuka S, Tawara I, Shimizu J, Sakaguchi S, Fujita T, Nakayama E (1999) Tumor rejection by in vivo administration of anti-CD25 (interleukin-2 receptor alpha) monoclonal antibody. Cancer Res 59:3128–3133

    PubMed  CAS  Google Scholar 

  23. O’Reilly M, Rosenthal R, Sage E, Smith S, Holmgren L, Moses M et al (1993) The suppression of tumor metastases by a primary tumor. Surg Forum 44:474–478

    Google Scholar 

  24. Ribas A, Timmerman JM, Butterfield LH, Economou JS (2003) Determinant spreading and tumor responses after peptide-based cancer immunotherapy. Trends Immunol 24:58–61

    Article  PubMed  CAS  Google Scholar 

  25. Rosenberg SA (2004) Shedding light on immunotherapy for cancer. N Engl J Med 350:1461–1463

    Article  PubMed  CAS  Google Scholar 

  26. Saeki H, Moore AM, Brown MJ, Hwang ST (1999) Cutting edge: secondary lymphoid-tissue chemokine (SLC) and CC chemokine receptor 7 (CCR7) participate in the emigration pathway of mature dendritic cells from the skin to regional lymph nodes. J Immunol 162:2472–2475

    PubMed  CAS  Google Scholar 

  27. Shimizu J, Yamazaki S, Sakaguchi S (1999) Induction of tumor immunity by removing CD25+CD4+ T cells: a common basis between tumor immunity and autoimmunity. J Immunol 163:5211–5218

    PubMed  CAS  Google Scholar 

  28. Sugarbaker E, Thornthwaite J, Ketcham A (1977) Inhibitor effect of a primary tumor on metastasis. In: Day S et al (eds) Progress in cancer research and therapy. Raven, New York pp 227–240

    Google Scholar 

  29. Sutmuller RP, van Duivenvoorde LM, van Elsas A, Schumacher TN, Wildenberg ME, Allison JP et al (2001) Synergism of cytotoxic T lymphocyte-associated antigen 4 blockade and depletion of CD25(+) regulatory T cells in antitumor therapy reveals alternative pathways for suppression of autoreactive cytotoxic T lymphocyte responses. J Exp Med 194:823–832

    Article  PubMed  CAS  Google Scholar 

  30. Topalian SL, Solomon D, Rosenberg SA (1989) Tumor-specific cytolysis by lymphocytes infiltrating human melanomas. J Immunol 142:3714–3725

    PubMed  CAS  Google Scholar 

  31. Turk MJ, Guevara-Patino JA, Rizzuto GA, Engelhorn ME, Houghton AN (2004) Concomitant tumor immunity to a poorly immunogenic melanoma is prevented by regulatory T cells. J Exp Med 200:771–782

    Article  PubMed  CAS  Google Scholar 

  32. Wiley H, Gonzalez EB, Maki W, Wu M, Hwang ST (2001) Expression of CC chemokine receptor-7 (CCR7) and regional lymph node metastasis of B16 murine melanoma. J Natl Cancer Inst 93:1638–1643

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We wish to thank Dr. Mark C. Udey (NCI) and Dr. Nicholas Restifo (NCI) for helpful comments and suggestions. Dr. Seth Steinberg (NCI) generously aided with statistical advice. This work was supported by funds from the Center for Cancer Research, National Cancer Institute. HN was supported by Clinical Research Training Program, NIH, and GP was supported by a Howard Hughes Medical Student Fellowship.

Author information

Authors and Affiliations

  1. Laboratory of Parasitic Diseases, NIAID, Bethesda, MD, 20892, USA

    Gulnar Pothiawala & Yasmine Belkaid

  2. Metabolism Branch, Center for Cancer Research, NCI, Bethesda, MD, 20892, USA

    Hisataka Kobayashi

  3. Surgery Branch, Center for Cancer Research, NCI, Bethesda, MD, 20892, USA

    Steven E. Finkelstein

  4. Dermatology Branch, Center for Cancer Research, NCI, Bldg 10/Rm12N246, 10 Center Dr., Bethesda, MD, 20892-1908, USA

    Takashi Kakinuma, Hari Nadiminti, Anke S. Lonsdorf, Takashi Murakami, Bradford A. Perez & Sam T. Hwang

Authors
  1. Takashi Kakinuma
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hari Nadiminti
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Anke S. Lonsdorf
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Takashi Murakami
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Bradford A. Perez
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hisataka Kobayashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Steven E. Finkelstein
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Gulnar Pothiawala
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Yasmine Belkaid
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Sam T. Hwang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Sam T. Hwang.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kakinuma, T., Nadiminti, H., Lonsdorf, A.S. et al. Small numbers of residual tumor cells at the site of primary inoculation are critical for anti-tumor immunity following challenge at a secondary location. Cancer Immunol Immunother 56, 1119–1131 (2007). https://doi.org/10.1007/s00262-006-0253-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00262-006-0253-4

Keywords

Search

Navigation