Background Although Malignant Cutaneous Melanoma (CM) is a highly immunogenic cancer, it can evade the immune system by forming an immunosuppressive tumor microenvironment (TME). FoxP3+ Regulatory T cells (Tregs) and indoleamine-2,3-dioxygenase (IDO) are a part of the immunosuppressive TME in CM. In previous studies, IDO expression correlates with poor prognosis and greater Breslow’s depth, but results concerning the role of FoxP3+ Tregs in CM have been controversial. Furthermore, the correlation between IDO and Tregs has not been substantially studied in CM, although IDO is known to be an important regulator of Tregs activity. To develop new therapeutic strategies, it is important to understand the role of immunosuppressive factors in CM.
Materials and Methods We investigated the associations of FoxP3+ Tregs, IDO+ tumor cells and IDO+ stromal immune cells with tumor stage, prognostic factors, and survival in CM. FoxP3 and IDO were immunohistochemically stained from 29 benign and 29 dysplastic nevi, 18 in situ -melanomas, 48 superficial and 62 deep melanomas and 67 lymph node metastases of CM. The number of FoxP3+ Tregs and IDO+ stromal immune cells was analysed quantitatively and the coverage and intensity of IDO+ tumor cells was evaluated semiquantitatively. Tumors were divided into IDO-negative and IDO-positive, containing less or more than 1% IDO+ melanoma cells of all tumor cells, respectively. P values equal to or less than 0.05 were considered statistically significant.
Results IDO+ stromal immune cells and FoxP3+ Tregs mainly accumulated in the areas with lymphocyte infiltration and thus resided mostly in the perilesional stroma. The number of FoxP3+ Tregs and IDO+ stromal immune cells were significantly higher in malignant melanomas compared with benign lesions. The increased expression of IDO in melanoma cells was associated with poor prognostic factors, such as recurrence, nodular growth pattern and increased mitotic count. Furthermore, the expression of IDO in melanoma cells was associated with reduced recurrence-free survival. We further showed that IDO-positive tumors contained significantly higher amounts of FoxP3+ Tregs and IDO+ stromal immune cells than IDO-negative tumors. However, the correlation between FoxP3+ Treg and IDO+ stromal immune cell counts was rather weak.
Conclusions Our results indicate that IDO expression is intimately involved in creating a TME conducive to tumor growth in CM. Thus, targeting IDO enzymatic pathway might be a worth of further studies in CM. Furthermore, we show that FoxP3+ Tregs appear to contribute to the immunosuppressive TME in CM, but their role may not be that critical to melanoma progression. The positive association of FoxP3+ Tregs with IDO+ melanoma cells, but not with IDO+ stromal immune cells, indicates a complex interaction between IDO and Tregs in CM, which demands further studies. Support: Sigrid Juselius Foundation (S.P.-S.), Academy of Finland (S.P.-S.), The Paavo Koistinen Foundation (S.S.), Emil Aaltonen Foundation (S.S.) and North-Savo Cultural Foundation (S.S.).
Disclosure Information S. Salmi: None. A. Lin: None. B. Hirschovits-Gerz: None. M. Valkonen: None. N. Aaltonen: None. R. Sironen: None. H. Siiskonen: None. S. Pasonen-Seppänen: None.
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