Skip to main content
Log in

Disarming suppressor cells to improve immunotherapy

  • Focussed Research Review
  • Published:
Cancer Immunology, Immunotherapy Aims and scope Submit manuscript


Human tumors can use many different mechanisms to induce dysfunction in the host immune system. Accumulations of inducible regulatory T cells (iTreg, Tr1) are commonly seen in the tumor microenvironment. These Treg express CD39 and up-regulate CD73 ectonucleotidases, hydrolyze exogenous adenosine triphosphate (ATP) to AMP and adenosine and produce prostaglandin E2 (PGE2). Most tumors also express CD39/CD73 and COX-2 and thus contribute to immune suppression. Pharmacologic inhibitors can be used to eliminate adenosine/PGE2 production by Tr1 as well as the tumor or to block binding of these factors to their receptors on Teff or to selectively block cAMP synthesis in Teff. These pharmacologic blocking strategies used alone or in combination with conventional treatments or immunotherapies could disarm Tr1, at the same time restoring antitumor functions of Teff.

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

Access this article

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

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others


  1. Gershon RK (1975) A disquisition on suppressor T cells. Transpl Rev 26:170–185

    CAS  Google Scholar 

  2. Czystowska M, Strauss L, Bergmann C, Szajnik M, Rabinowich H, Whiteside TL (2010) Reciprocal granzyme/perforin-mediated death of human regulatory and responder T cells is regulated by interleukin-2 (IL-2). J Mol Med 88:577–588

    Article  PubMed  CAS  Google Scholar 

  3. Strauss L, Bergmann C, Whiteside TL (2009) Human circulating CD4+CD25highFoxp3+ Treg kill autologous CD8+ but not CD4+ responder cells by Fas-mediated apoptosis. J Immunol 182:1469–1480

    PubMed  CAS  Google Scholar 

  4. Shevach EM (2009) Mechanisms of Foxp3+ T regulatory cell-mediated suppression. Immunity 30:636–645

    Article  PubMed  CAS  Google Scholar 

  5. Sitkovsky MV, Kjaergaard J, Lukashev D, Ohta A (2008) Hypoxia-adenosinergic immunosuppression: tumor protection by T regulatory cells and cancerous tissue hypoxia. Clin Cancer Res 14:5947–5952

    Article  PubMed  CAS  Google Scholar 

  6. Raimondi G, Turner MS, Thomson AW, Morel PA (2007) Naturally occurring regulatory T cells: recent insights in health and disease. Crit Rev Immunol 27:61–95

    PubMed  CAS  Google Scholar 

  7. Roncarolo MG, Gregori S, Battaglia M, Bacchetta R, Fleischhauer K, Levings MK (2006) Interleukin-10 secreting type 1 regulatory T cells in rodents and humans. Immunol Rev 212:28–50

    Article  PubMed  CAS  Google Scholar 

  8. Bergmann C, Strauss L, Zeidler R, Lang S, Whiteside TL (2007) Expansion of human T regulatory type 1 cells in the microenvironment of cyclooxygenase 2 overexpressing head and neck squamous cell carcinoma. Cancer Res 67:8865–8873

    Article  PubMed  CAS  Google Scholar 

  9. Roncarolo MG, Bacchetta R, Bordignon C, Narula S, Levings MK (2001) Type 1 T regulatory cells. Immunol Rev 182:68–79

    Article  PubMed  CAS  Google Scholar 

  10. Curiel TJ, Coukos G, Zou L, Alvarez X, Cheng P, Mottram P, Evdemon-Hogan M, Conejo-Garcia JR, Zhang L, Burow M, Zhu Y, Wei S, Kryczek I, Daniel B, Gordon A, Myers L, Lackner A, Disis ML, Knutson KL, Chen L, Zou W (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 

  11. Strauss L, Bergmann C, Szczepanski M, Gooding W, Johnson JT, Whiteside TL (2007) A unique subset of CD4+CD25highFoxp3+ T cells secreting IL-10 and TGF-β1 mediates suppression in the tumor microenvironment. Clin Cancer Res 13:4345–4354

    Article  PubMed  CAS  Google Scholar 

  12. Eggermont AM (2009) Immunostimulation versus immunosuppression after multiple vaccinations: the woes of therapeutic vaccine development. Clin Cancer Res 15:6745–6747

    Article  PubMed  CAS  Google Scholar 

  13. DeVries IJ, Castelli C, Huygens C, Jacobs JF, Stockis J, Schuler-Thurner B, Adema GJ, Punt CJ, Rivoltini L, Schuler G, Coulie PG, Luca SS (2010) Frequency of circulating Tregs with demethylated FOXP3 intron 1 in melanoma patients receiving tumor vaccines and potentially Treg-depleting agents. Clin Cancer Res 17:1–8

    Google Scholar 

  14. Whiteside TL (2008) The tumor microenvironment and its role in promoting tumor growth. Oncogene 27:5904–5912

    Article  PubMed  CAS  Google Scholar 

  15. Dwyer KM, Deaglio S, Gao W, Friedman D, Strom TB, Robson SC (2007) CD39 and control of cellular immune responses. Purinergic Signal 3:171–180

    Article  PubMed  CAS  Google Scholar 

  16. Hoskin DW, Mader JS, Furlong SJ, Conrad DM, Blay J (2008) Inhibition of T cell and natural killer cell function by adenosine and its contribution to immune evasion by tumor cells (Review). Int J Oncol 32:527–535

    PubMed  CAS  Google Scholar 

  17. Borsellino G, Kleinewietfeld M, Di Mitri D, Sternjak A, Diamantini A, Giometto R, Hopner S, Centonze D, Bernardi G, Dell’Acqua ML, Rossini PM, Battistini L, Rotzschke O, Falk K (2007) Expression of ectonucleotidase CD39 by Foxp3+ Treg cells: hydrolysis of extracellular ATP and immune suppression. Blood 110:1225–1232

    Article  PubMed  CAS  Google Scholar 

  18. Deaglio S, Dwyer KM, Gao W, Friedman D, Usheva A, Erat A, Chen JF, Enjyoji K, Linden J, Oukka M, Kuchroo VK, Strom TB, Robson SC (2007) Adenosine generation catalyzed by CD39 and CD73 expressed on regulatory T cells mediates immune suppression. J Exp Med 204:1257–1265

    Article  PubMed  CAS  Google Scholar 

  19. Bynoe MS, Viret C (2008) FoxP3+CD4+ T cell-mediated immunosuppression involves extracellular nucleotide metabolism. Trends Immunol 29:99–102

    Article  PubMed  CAS  Google Scholar 

  20. Mandapathil M, Hilldorfer B, Szczepanski MJ, Czystowska M, Szajnik M, Ren J, Lang S, Jackson EK, Gorelik E, Whiteside TL (2010) Generation and accumulation of immunosuppressive adenosine by human CD4+CD25highFOXP3+ regulatory T cells. J Biol Chem 285:7176–7186

    Article  PubMed  CAS  Google Scholar 

  21. Schuler P, Harasymczuk M, Schilling B, Lang S, Whiteside TL (2011) Separation of human CD4+CD39+ T cells by magnetic beads reveals two phenotypically and functionally different subsets. J Immunol Meth 369:59–68

    Article  CAS  Google Scholar 

  22. Bergmann C, Strauss L, Zeidler R, Lang S, Whiteside TL (2007) Expansion and characteristics of human T regulatory type 1 cells in co-cultures simulating tumor microenvironment. Cancer Immunol Immunother 56:1429–1442

    Article  PubMed  Google Scholar 

  23. Mandapathil M, Szczepanski MJ, Szajnik M, Ren J, Jackson EK, Johnson JT, Gorelik E, Lang S, Whiteside TL (2010) Adenosine and prostaglandin E2 cooperate in the suppression of immune responses mediated by adaptive regulatory T cells. J Biol Chem 285:27571–27580

    Article  PubMed  CAS  Google Scholar 

  24. Zhang B (2010) CD73: a novel target for cancer immunotherapy. Cancer Res 70:6407–6411

    Article  PubMed  CAS  Google Scholar 

  25. Mandapathil M, Whiteside TL (2011) Targeting human inducible regulatory T cells (Tr1) in patients with cancer: blocking of adenosine-prostaglandin E2 cooperation. Expert Opin Biol Ther 11:1203–1214

    Article  PubMed  CAS  Google Scholar 

  26. Hausler SF, Montalban Del Barrio I, Strohschein J et al (2011) Ectonucleotidases CD39 and CD73 on OvCA cells are potent adenosine-generating enzymes responsible for adenosine receptor2A-dependent suppression of T-cell function and NK cell cytotoxicity. Cancer Immunol Immunother 60(10):1405–1418

    Article  PubMed  Google Scholar 

  27. Yaqub S, Tasken K (2008) Role for the cAMP-protein kinase A signaling pathway in suppression of anti-tumor immune responses by regulatory T cells. Crit Rev Oncog 14:57–77

    PubMed  Google Scholar 

Download references

Conflict of interest

The author declares that she has no conflict of interest.

Author information

Authors and Affiliations


Corresponding author

Correspondence to Theresa L. Whiteside.

Additional information

This paper is a Focussed Research Review based on a presentation given at the Second International Conference on Cancer Immunotherapy and Immunomonitoring (CITIM 2011), held in Budapest, Hungary, May 2–5, 2011. It is part of a CII series of Focussed Research Reviews and meeting report.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Whiteside, T.L. Disarming suppressor cells to improve immunotherapy. Cancer Immunol Immunother 61, 283–288 (2012).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: