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
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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.