Suppression of tumour-specific CD4+ T cells by regulatory T cells is associated with progression of human colorectal cancer
- Gareth Betts1,
- Emma Jones1,
- Syed Junaid1,
- Tariq El-Shanawany1,
- Martin Scurr1,
- Paul Mizen1,
- Mayur Kumar1,
- Sion Jones1,
- Brian Rees2,
- Geraint Williams3,
- Awen Gallimore1,
- Andrew Godkin1
- 1Department of Infection, Immunity and Biochemistry, School of Medicine, Cardiff University, Cardiff, UK
- 2Department of Surgery, University Hospital of Wales, Cardiff, UK
- 3Department of Pathology, School of Medicine, Cardiff University, Cardiff, UK
- Correspondence to Dr Andrew Godkin, Department of Infection, Immunity and Biochemistry, School of Medicine, Henry Wellcome Building, Cardiff University, Cardiff CF144XN, UK; godkinaj{at}cf.ac.uk
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Contributors Research design: AJG, AMG, GB, EJ. Performed experimental work: GB, EJ, SJ, TE-S, MS, PM, MK, SJ. Provision of samples: BR, GW. Wrote paper: AMG, AJG.
- Accepted 16 September 2011
- Published Online First 29 December 2011
Abstract
Background There is indirect evidence that T cell responses can control the metastatic spread of colorectal cancer (CRC). However, an enrichment of CD4+Foxp3+ regulatory T cells (Tregs) has also been documented.
Objective To evaluate whether CRC promotes Treg activity and how this influences anti-tumour immune responses and disease progression.
Methods A longitudinal study of Treg activity on a cohort of patients was performed before and after tumour resection. Specific CD4+ T cell responses were also measured to the tumour associated antigens carcinoembryonic antigen (CEA) and 5T4.
Results Tregs from 62 preoperative CRC patients expressed a highly significant increase in levels of Foxp3 compared to healthy age-matched controls (p=0.007), which returned to normal after surgery (p=0.0075). CD4+ T cell responses to one or both of the tumour associated antigens, CEA and 5T4, were observed in approximately two-thirds of patients and one third of these responses were suppressed by Tregs. Strikingly, in all patients with tumour recurrence at 12 months, significant preoperative suppression was observed of tumour-specific (p=0.003) but not control CD4+ T cell responses.
Conclusion These findings demonstrate that the presence of CRC drives the activity of Tregs and accompanying suppression of CD4+ T cell responses to tumour-associated antigens. Suppression is associated with recurrence of tumour at 12 months, implying that Tregs contribute to disease progression. These findings offer a rationale for the manipulation of Tregs for therapeutic intervention.
- Regulatory T cells
- colorectal cancer
- imaging
- T lymphocytes
- colorectal cancer
- colorectal diseases
- histopathology
- cancer immunobiology
- hepatitis
- immunoregulation
- hepatitis C
- α β T cells
- hepatitis B
Footnotes
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The authors Awen Gallimore and Andrew Godkin contributed equally to this work.
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Funding This work was supported by grants from the Tenovus Cancer Charity and Cancer Research Wales and an MRC grant awarded to AG (G0801190). AG is supported by a Wellcome Trust University Award (086983/Z/08/Z). This work was also supported by kind donations from Sir Stanley and Lady Shirley Thomas.
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Competing interests None.
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Ethics approval Ethics approval was provided by South East Wales Ethics Committee.
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Provenance and peer review Not commissioned; externally peer reviewed.
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