Data for this Review were identified by searches of PubMed with the search terms “melanoma”, “immunotherapy”, and “regulatory T cell”. References from relevant articles indentified by this strategy were included. Abstracts and reports from meetings were included only when they related directly to previously published work. Only papers published in English were included, without additional limitations. The last search was done in February, 2011.
ReviewRegulatory T cells in melanoma: the final hurdle towards effective immunotherapy?
Section snippets
Melanoma and immunity
Worldwide, the incidence of malignant melanoma is steadily increasing, with a growing proportion of patients showing advanced disease for which the outlook is very poor.1 Melanomas are less sensitive to standard treatment options, such as radiotherapy and chemotherapy, than other cancers. As a result, no therapeutic regimens that greatly prolong survival of patients with melanoma are available.2 Alternative treatment opportunities or combination cancer therapies that will improve effectiveness
Treg in patients with melanoma
Several investigations have shown that Treg are over-represented in peripheral blood of patients with metastatic melanoma, compared with age-matched healthy controls (table).16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28 Treg in patients with melanoma are highly enriched in the tumour microenvironment including primary lesions,23, 24, 25, 26, 27 affected lymph nodes,20 and metastatic lesions (table).20, 27, 28 The Treg in these patients are reported to be functionally immunosuppressive.20,
Treg in melanoma and immunotherapy
Treg-mediated immunosuppression is generally deemed one of the main hurdles for cancer immunotherapy. The ability to modulate selectively Treg in vivo is therefore a potential treatment option to augment antitumour immune responses (figure 3).15, 41, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63
Treg-modulating strategies
Other molecules have been identified on the surface of Treg, such as GITR, CTLA-4, CD103 or LAG3, and OΩ40, but like CD25, they are not exclusively expressed on Treg.
Future perspectives
The synergistic beneficial effect of Treg depletion combined with therapeutic cancer vaccines as observed in murine studies has not been convincingly shown in patients with melanoma. In a multicentre trial we compared the efficiency of three potentially Treg-depleting agents given to patients with melanoma by measuring naturally occurring Treg frequencies in blood with a molecular assay. Our results show that neither daclizumab, nor low-dose cyclophosphamide or denileukin diftitox induced a
Conclusions
Accumulation of Treg in patients with melanoma is a major factor in tumour immune escape. As a result, targeting of these cells could provide a mechanism by which antitumour immune function can be restored. In general terms, most of the immunotherapeutic strategies that target Treg in animal studies seem to shift the immune balance in favour of effective anti-cancer immune responses. Up to now, these interventions have not completely fulfilled their promise in human studies. Effective melanoma
Search strategy and selection criteria
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Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival
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Expression of indoleamine 2,3-dioxygenase in metastatic malignant melanoma recruits regulatory T cells to avoid immune detection and affects survival
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These authors contributed equally