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;
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
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
- T lymphocytes
- colorectal cancer
- colorectal diseases
- cancer immunobiology
- hepatitis C
- α β T cells
- hepatitis B
The authors Awen Gallimore and Andrew Godkin contributed equally to this work.
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.
Competing interests None.
Ethics approval Ethics approval was provided by South East Wales Ethics Committee.
Provenance and peer review Not commissioned; externally peer reviewed.
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