Skip to main content

Advertisement

SpringerLink
Log in

Regulatory T-cell-mediated inhibition of antitumor immune responses is associated with clinical outcome in patients with liver metastasis from colorectal cancer

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

Abstract

Adaptive regulatory T cells (Tregs) contribute to an immunosuppressive microenvironment in colorectal cancer (CRC). Here, we examined whether the level of Treg-mediated inhibition of antitumor immune responses in patients with metastatic CRC (metCRC) selected for liver resection is associated with clinical outcome. Preoperatively and at follow-ups, we did flow-based phenotyping, examined antitumor immunity using peptides from carcinoembryonic antigen (CEA) protein in the presence or absence of CD4+CD25+CD127dim/− cells (Tregs) and determined cytokine and PGE2 levels in patient blood samples. At 18 months post-surgery, 8 patients were disease free (7 alive and 1 dead of unrelated cause) and 10 had experienced disease recurrence (7 alive and 3 dead of metCRC). Prior to surgery, the patients demonstrated Treg-mediated suppression of TNFα and IFNγ expression that could be perturbed through the PGE2/cAMP pathway and the immune suppression was significantly higher in the group that later developed disease recurrence (P = 0.046). Furthermore, the post-surgery plasma PGE2 levels were related to the clinical outcome (PGE2 levels of 280 ± 47 vs. 704 ± 153 pg/ml (mean ± SEM) for disease free and recurrent disease, respectively). T-cell phenotyping revealed higher frequencies of COX-2+ cells in the patients with recurrent disease. These findings support the notion that the level of Treg-mediated suppression of adaptive antitumor immune responses at the time of surgery may influence later clinical outcome of metCRC and provide valuable prognostic information.

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

Similar content being viewed by others

References

  1. Karsa LV, Lignini TA, Patnick J, Lambert R, Sauvaget C (2010) The dimensions of the CRC problem. Best Pract Res Clin Gastroenterol 24:381–396

    Article  PubMed  CAS  Google Scholar 

  2. LeGolvan MP, Resnick M (2010) Pathobiology of colorectal cancer hepatic metastases with an emphasis on prognostic factors. J Surg Oncol 102:898–908

    Article  PubMed  Google Scholar 

  3. Lewis AM, Martin RC (2006) The treatment of hepatic metastases in colorectal carcinoma. Am Surg 72:466–473

    PubMed  Google Scholar 

  4. Dimitroulis D, Nikiteas N, Troupis T, Patsouras D, Skandalakis P, Kouraklis G (2010) Role of surgery in colorectal liver metastases: too early or too late? World J Gastroenterol 16:3484–3490

    Article  PubMed  Google Scholar 

  5. Yaqub S, Henjum K, Mahic M, Jahnsen FL, Aandahl EM, Bjornbeth BA, Tasken K (2008) Regulatory T cells in colorectal cancer patients suppress anti-tumor immune activity in a COX-2 dependent manner. Cancer Immunol Immunother 57:813–821

    Article  PubMed  CAS  Google Scholar 

  6. Fujino H, Toyomura K, Chen Xb, Regan JW, Murayama T (2011) Prostaglandin E2 regulates cellular migration via induction of vascular endothelial growth factor receptor-1 in HCA-7 human colon cancer cells. Biochem Pharmacol 81:379–387

    Article  PubMed  CAS  Google Scholar 

  7. Sheng H, Shao J, Morrow JD, Beauchamp RD, DuBois RN (1998) Modulation of apoptosis and Bcl-2 expression by prostaglandin E2 in human colon cancer cells. Cancer Res 58:362–366

    PubMed  CAS  Google Scholar 

  8. Sheng H, Shao J, Washington MK, DuBois RN (2001) Prostaglandin E2 increases growth and motility of colorectal carcinoma cells. J Biol Chem 276:18075–18081

    Article  PubMed  CAS  Google Scholar 

  9. Tsujii M, Kawano S, DuBois RN (1997) Cyclooxygenase-2 expression in human colon cancer cells increases metastatic potential. Proc Natl Acad Sci USA 94:3336–3340

    Article  PubMed  CAS  Google Scholar 

  10. Tsujii M, Kawano S, Tsuji S, Sawaoka H, Hori M, DuBois RN (1998) Cyclooxygenase regulates angiogenesis induced by colon cancer cells. Cell 93:705–716

    Article  PubMed  CAS  Google Scholar 

  11. Mosenden R, Tasken K (2011) Cyclic AMP-mediated immune regulation - overview of mechanisms of action in T cells. Cell Signal 23:1009–1016

    Article  PubMed  CAS  Google Scholar 

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

    PubMed  Google Scholar 

  13. Kim R, Emi M, Tanabe K, Arihiro K (2006) Tumor-driven evolution of immunosuppressive networks during malignant progression. Cancer Res 66:5527–5536

    Article  PubMed  CAS  Google Scholar 

  14. Pages F, Berger A, Camus M, Sanchez-Cabo F, Costes A, Molidor R, Mlecnik B, Kirilovsky A, Nilsson M, Damotte D, Meatchi T, Bruneval P, Cugnenc PH, Trajanoski Z, Fridman WH, Galon J (2005) Effector memory T cells, early metastasis, and survival in colorectal cancer. N Engl J Med 353:2654–2666

    Article  PubMed  CAS  Google Scholar 

  15. Galon J, Costes A, Sanchez-Cabo F, Kirilovsky A, Mlecnik B, Lagorce-Pages C, Tosolini M, Camus M, Berger A, Wind P, Zinzindohoue F, Bruneval P, Cugnenc PH, Trajanoski Z, Fridman WH, Pages F (2006) Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science 313:1960–1964

    Article  PubMed  CAS  Google Scholar 

  16. Clarke SL, Betts GJ, Plant A, Wright KL, El-Shanawany TM, Harrop R, Torkington J, Rees BI, Williams GT, Gallimore AM, Godkin AJ (2006) CD4+CD25+FOXP3+ regulatory T cells suppress anti-tumor immune responses in patients with colorectal cancer. PLoS One 1:e129

    Article  PubMed  Google Scholar 

  17. Bonertz A, Weitz J, Pietsch DH, Rahbari NN, Schlude C, Ge Y, Juenger S, Vlodavsky I, Khazaie K, Jaeger D, Reissfelder C, Antolovic D, Aigner M, Koch M, Beckhove P (2009) Antigen-specific Tregs control T cell responses against a limited repertoire of tumor antigens in patients with colorectal carcinoma. J Clin Invest 119:3311–3321

    PubMed  CAS  Google Scholar 

  18. Steer HJ, Lake RA, Nowak AK, Robinson BW (2010) Harnessing the immune response to treat cancer. Oncogene 29:6301–6313

    Article  PubMed  CAS  Google Scholar 

  19. Mahic M, Yaqub S, Johansson CC, Taskén K, Aandahl EM (2006) FOXP3+CD4+CD25+ adaptive regulatory T cells express cyclooxygenase-2 and suppress effector T cells by a prostaglandin E2-dependent mechanism. J Immunol 177:246–254

    PubMed  CAS  Google Scholar 

  20. Cai Q, Gao YT, Chow WH, Shu XO, Yang G, Ji BT, Wen W, Rothman N, Li HL, Morrow JD, Zheng W (2006) Prospective study of urinary prostaglandin E2 metabolite and colorectal cancer risk. J Clin Oncol 24:5010–5016

    Article  PubMed  CAS  Google Scholar 

  21. Gupta RA, DuBois RN (2001) Colorectal cancer prevention and treatment by inhibition of cyclooxygenase-2. Nat Rev Cancer 1:11–21

    Article  PubMed  CAS  Google Scholar 

  22. Jacobs EJ, Thun MJ, Bain EB, Rodriguez C, Henley SJ, Calle EE (2007) A large cohort study of long-term daily use of adult-strength aspirin and cancer incidence. J Natl Cancer Inst 99:608–615

    Article  PubMed  CAS  Google Scholar 

  23. Sheng H, Shao J, Kirkland SC, Isakson P, Coffey RJ, Morrow J, Beauchamp RD, DuBois RN (1997) Inhibition of human colon cancer cell growth by selective inhibition of cyclooxygenase-2. J Clin Invest 99:2254–2259

    Article  PubMed  CAS  Google Scholar 

  24. Coussens LM, Werb Z (2002) Inflammation and cancer. Nature 420:860–867

    Article  PubMed  CAS  Google Scholar 

  25. 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 

  26. Nosho K, Baba Y, Tanaka N, Shima K, Hayashi M, Meyerhardt JA, Giovannucci E, Dranoff G, Fuchs CS, Ogino S (2010) Tumour-infiltrating T-cell subsets, molecular changes in colorectal cancer, and prognosis: cohort study and literature review. J Pathol 222:350–366

    Article  PubMed  Google Scholar 

  27. Frey DM, Droeser RA, Viehl CT, Zlobec I, Lugli A, Zingg U, Oertli D, Kettelhack C, Terracciano L, Tornillo L (2010) High frequency of tumor-infiltrating FOXP3(+) regulatory T cells predicts improved survival in mismatch repair-proficient colorectal cancer patients. Int J Cancer 126:2635–2643

    PubMed  CAS  Google Scholar 

  28. Salama P, Phillips M, Grieu F, Morris M, Zeps N, Joseph D, Platell C, Iacopetta B (2009) Tumor-infiltrating FOXP3+ T regulatory cells show strong prognostic significance in colorectal cancer. J Clin Oncol 27:186–192

    Article  PubMed  Google Scholar 

  29. Ling KL, Pratap SE, Bates GJ, Singh B, Mortensen NJ, George BD, Warren BF, Piris J, Roncador G, Fox SB, Banham AH, Cerundolo V (2007) Increased frequency of regulatory T cells in peripheral blood and tumour infiltrating lymphocytes in colorectal cancer patients. Cancer Immun 7:7

    PubMed  Google Scholar 

  30. Roncarolo MG, Gregori S (2008) Is FOXP3 a bona fide marker for human regulatory T cells? Eur J Immunol 38:925–927

    Article  PubMed  CAS  Google Scholar 

  31. Soler AP, Miller RD, Laughlin KV, Carp NZ, Klurfeld DM, Mullin JM (1999) Increased tight junctional permeability is associated with the development of colon cancer. Carcinogenesis 20:1425–1431

    Article  PubMed  CAS  Google Scholar 

  32. Ladoire S, Martin F, Ghiringhelli F (2011) Prognostic role of FOXP3+ regulatory T cells infiltrating human carcinomas: the paradox of colorectal cancer. Cancer Immunol Immunother 60:909–918

    Article  PubMed  CAS  Google Scholar 

  33. Ling KL, Pratap SE, Bates GJ, Singh B, Mortensen NJ, George BD, Warren BF, Piris J, Roncador G, Fox SB, Banham AH, Cerundolo V (2007) Increased frequency of regulatory T cells in peripheral blood and tumour infiltrating lymphocytes in colorectal cancer patients. Cancer Immun 7:7

    PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by the Norwegian Cancer Society and the Research Council of Norway. KWB is a fellow of the Norwegian Cancer Society.

Conflict of Interest

The authors declare no conflict of interest.

Author information

Authors and Affiliations

  1. Centre for Molecular Medicine Norway, Nordic EMBL Partnership and Biotechnology Centre, University of Oslo, Blindern, P.O. Box 1137, 0318, Oslo, Norway

    Kristoffer Watten Brudvik, Karen Henjum, Einar Martin Aandahl & Kjetil Taskén

  2. Section for Gastroenterology Surgery, Department of Surgery, Oslo University Hospital Ullevål, Oslo, Norway

    Karen Henjum & Bjørn Atle Bjørnbeth

  3. Section for Transplantation Surgery, Oslo University Hospital Rikshospitalet, Oslo, Norway

    Einar Martin Aandahl

Authors
  1. Kristoffer Watten Brudvik
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Karen Henjum
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Einar Martin Aandahl
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Bjørn Atle Bjørnbeth
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Kjetil Taskén
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Kjetil Taskén.

Additional information

Kristoffer Watten Brudvik and Karen Henjum contributed equally.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Brudvik, K.W., Henjum, K., Aandahl, E.M. et al. Regulatory T-cell-mediated inhibition of antitumor immune responses is associated with clinical outcome in patients with liver metastasis from colorectal cancer. Cancer Immunol Immunother 61, 1045–1053 (2012). https://doi.org/10.1007/s00262-011-1174-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00262-011-1174-4

Keywords

Search

Navigation