Elsevier

The Lancet Oncology

Volume 13, Issue 1, January 2012, Pages e32-e42
The Lancet Oncology

Review
Regulatory T cells in melanoma: the final hurdle towards effective immunotherapy?

https://doi.org/10.1016/S1470-2045(11)70155-3Get rights and content

Summary

Immunotherapy studies in patients with melanoma have reported success in the expansion of tumour-specific effector T cells in vivo, but even in the presence of substantial numbers of functional T cells circulating in the blood, favourable clinical outcomes are scarce. This failure to induce robust clinical responses might be related to tumour-induced immune evasion, rendering the host tolerant to melanoma antigens. Immunosuppression in the tumour microenvironment mediated by regulatory T cells (Treg) is a dominant mechanism of tumour immune escape and is a major hurdle for tumour immunotherapy. Accumulation of Treg in melanoma is frequently recorded and the ratio of CD8-positive T cells versus Treg in the tumour microenvironment is predictive for survival of patients with melanoma. Hence, depletion of Treg seems to be a promising strategy for the enhancement of melanoma-specific immunity. Indeed, murine studies have shown that Treg depletion greatly increases the efficacy of immunotherapy. But despite the success of some strategies in depletion of Treg in patients, overall clinical efficacy has been disappointing. The lack of Treg specificity of the Treg depleting strategies applied so far imply that well-designed studies into dosage, timing, and administration regimens with more specific agents are urgently needed. Depletion of functional Treg from the tumour microenvironment as part of multifaceted immunotherapeutic treatments is a major challenge to induce clinically relevant immune responses against melanomas.

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

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.

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