The role of FoxP3+ regulatory T cells and IDO+ immune and tumor cells in malignant melanoma \u2013 an immunohistochemical study

Satu Salmi,Sanna Pasonen-Seppänen,Hanna Siiskonen,Niina Aaltonen,Reijo Sironen,Benjamin Hirschovits-Gerz,Mari Valkonen,Anton Lin

doi:10.1186/s12885-021-08385-4

Satu Salmi, Sanna Pasonen-Seppänen + Show 6 more

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https://doi.org/10.1186/s12885-021-08385-4

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Abstract

BackgroundFoxP3+ Regulatory T cells (Tregs) and indoleamine-2,3-dioxygenase (IDO) participate in the formation of an immunosuppressive tumor microenvironment (TME) in malignant cutaneous melanoma (CM). Recent studies have reported that 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.MethodsWe 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 (LNMs) of CM. The number of FoxP3+ Tregs and IDO+ stromal immune cells, and the coverage and intensity of IDO+ tumor cells were analysed.ResultsThe 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 there was a positive correlation between IDO+ tumor cells and FoxP3+ Tregs.ConclusionsThese results indicate that IDO is strongly involved in melanoma progression. FoxP3+ Tregs also seems to contribute to the immunosuppressive TME in CM, but their significance in melanoma progression remains unclear. 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.

Highlights

Forkhead box P3-transcription factor (FoxP3)+ Regulatory T cells (Tregs) and indoleamine-2,3-dioxygenase (IDO) participate in the formation of an immunosuppressive tumor microenvironment (TME) in malignant cutaneous melanoma (CM)
FoxP3+ Tregs and IDO+ stromal immune cells are more abundant in malignant melanoma compared with benign lesions Melanoma specimens were stained for FoxP3 and IDO to examine the number and localization of FoxP3+ Tregs and IDO+ stromal immune cells
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

Summary

Introduction

FoxP3+ Regulatory T cells (Tregs) and indoleamine-2,3-dioxygenase (IDO) participate in the formation of an immunosuppressive tumor microenvironment (TME) in malignant cutaneous melanoma (CM). Recent studies have reported that IDO expression correlates with poor prognosis and greater Breslow’s depth, but results concerning the role of FoxP3+ Tregs in CM have been controversial. Immune evasion results from several factors that weaken the effect of melanomaspecific effector T cells. These factors include antiinflammatory cytokines, such as IL-10, defects in antigen presentation of melanoma cells and expression of immune checkpoint molecules, such as PD-L1 and CTLA-4. Tumor immunosuppression results from the presence of immunosuppressive cells, such as tumorassociated macrophages (TAMs) and regulatory T cells (Tregs), as well as cells that express amino-acid catabolizing enzymes like indoleamine-2,3-dioxygenase (IDO) [3]

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