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Colorectal tumourigenesis is in the majority of cases regarded as a multistep process resulting in chromosomal instability.1 High-frequency microsatellite instability (MSI-H) can be detected in ∼15–20% of all sporadic colorectal cancers (CRCs) and represents the hallmark of the hereditary non-polyposis colorectal cancer (HNPCC) syndrome. CRCs with MSI-H are caused by inactivation of DNA mismatch repair (MMR) genes leading to hundreds of insertion or deletion mutations in short segments of repeated nucleotide sequences, but no chromosomal instability. It has been speculated that abnormal peptides are generated as a consequence of these frameshift mutations, and one would expect a stimulation of the antitumour response by these tumour-associated antigens (TAAs).2 3 In fact, CRCs with MSI-H are associated with a markedly increased number of tumour-infiltrating lymphocytes (TILs) as compared with microsatellite-stable (MSS) tumours, and the favourable prognosis of patients with MSI-H cancer has been attributed to the high content of cytotoxic T cells.4
Over the past few years, CD4+CD25+ regulatory T cells (Treg cells) expressing the transcription factor forkhead box P3 (Foxp3) have been demonstrated to suppress T cell-mediated immunity to TAAs in various human tumours—for example, ovarian cancer.5 In mouse models, depletion of Treg cells using treatment with CD25-, GITR- or CTLA4-specific antibodies has resulted in improved antitumour immunity.6 In human CRC tissue samples, increased numbers of Treg cells as compared with normal mucosa have also been described, with a Treg cell infiltration rate slightly higher in patients without a systemic TAA-specific immune reaction.7 Despite successful induction of an immunological response, current protocols of immunotherapy and vaccination in CRC are not satisfactory.8 The poor response rate in patients with CRC may in part be due to the fact that immunosuppressive mechanisms conferred by Treg cells outweigh the beneficial effects of …
Competing interests: None.
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