Cancer Immunology, Immunotherapy

, Volume 57, Issue 6, pp 813–821 | Cite as

Regulatory T cells in colorectal cancer patients suppress anti-tumor immune activity in a COX-2 dependent manner

  • Sheraz Yaqub
  • Karen Henjum
  • Milada Mahic
  • Frode L. Jahnsen
  • Einar M. Aandahl
  • Bjørn A. Bjørnbeth
  • Kjetil Taskén
Original Article

Abstract

Objective

Naturally occurring regulatory T (TR) cells suppress autoreactive T cells whereas adaptive TR cells, induced in the periphery, play an important role in chronic viral diseases and cancer. Several studies indicate that cyclooxygenase (COX) inhibitors prevent cancer development of colon adenomas and delay disease progression in patients with colorectal cancer (CRC). We have shown that adaptive TR cells express COX-2 and produce PGE2 that suppress effector T cells in a manner that is reversed by COX-inhibitors.

Methods and results

Here we demonstrate that CRC patients have elevated levels of PGE2 in peripheral blood, and CRC tissue samples and draining lymph nodes display increased numbers of FOXP3+ TR cells. Depletion of TR cells from PBMC enhanced anti-tumor T-cell responses to peptides from carcinoembryonic antigen. Furthermore, the COX inhibitor indomethacin and the PKA type I antagonist Rp-8-Br-cAMPS significantly improved the anti-tumor immune activity.

Conclusion

We suggest that adaptive TR cells contribute to an immunosuppressive microenvironment in CRC and inhibit effector T cells by a COX-2–PGE2-dependent mechanism and thereby facilitate tumor growth. Therapeutic strategies targeting TR cells and the PGE2–cAMP pathway may be interesting to pursue to enhance anti-tumor immune activity in CRC patients.

Keywords

Human Colorectal cancer Regulatory T cells COX-2 PGE2 

Abbreviations

CEA

Carcinoembryonic antigen

COX-2

Cyclooxygenase type 2

CRC

Colorectal cancer

PGE2

Prostagandin E2

TR cells

Regulatory T cells

Notes

Acknowledgments

We are grateful for the routine pathology data made available from Department of Pathology, Ullevaal University Hospital and technical assistance with preparation of tissue specimens and multicolor immunostaining by Linda Kristiansen, Vigdis Wendel, and Aaste Aursjo (The Pathology Clinic, Rikshospitalet-Radiumhospitalet Medical Center). This work was supported by grants from the Norwegian Functional Genomics Programme (FUGE), The Research Council of Norway, The Norwegian Cancer Society, Novo Nordic Foundation Committee, and the European Union grant no. 037189. S. Yaqub and M. Mahic are fellows of the Norwegian Cancer Society.

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Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • Sheraz Yaqub
    • 1
    • 2
  • Karen Henjum
    • 1
    • 2
    • 3
  • Milada Mahic
    • 1
    • 2
  • Frode L. Jahnsen
    • 4
  • Einar M. Aandahl
    • 1
    • 2
  • Bjørn A. Bjørnbeth
    • 3
  • Kjetil Taskén
    • 1
    • 2
  1. 1.The Biotechnology Centre of OsloUniversity of OsloOsloNorway
  2. 2.Centre for Molecular Medicine Norway, Nordic EMBL PartnershipUniversity of OsloOsloNorway
  3. 3.Department of Gastroenterological SurgeryUllevaal University HospitalOsloNorway
  4. 4.The Pathology ClinicRikshospitalet-Radiumhospitalet Medical CenterOsloNorway

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