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

Abstract

Background 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. 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. 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 (LNMs) of CM. The number of FoxP3+ Tregs and IDO+ stromal immune cells, and the coverage and intensity of IDO+ tumor cells were analysed. Results 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 there was a positive correlation between IDO+ tumor cells and FoxP3+ Tregs. Conclusions These 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.

The Association of CD8+ Cytotoxic T Cells and Granzyme B+ Lymphocytes with Immunosuppressive Factors, Tumor Stage and Prognosis in Cutaneous Melanoma

“…Stainings for CD68 and CD163 have been described in [ 24 ]. Stainings for IDO and FoxP3 have been described in [ 25 ].…”

“…CD8 and GrB stainings were analyzed using the hotspot method described earlier [ 24 , 25 ]. The slides were scanned with a whole-slide digital scanner (Hamamatsu NanoZoomer S360).…”

“…An automated computed vision (CV) software reported earlier was used to analyze CD8+ lymphocytes from the images [ 25 ]. The software was added with the option to manually correct the selections of the CV.…”

“…The purpose of this study was to investigate the associations of CD8+ and GrB+ lymphocytes as well as tumor and stromal PD-L1 expression with tumor stage, prognosis and clinicopathological parameters in CM. Moreover, their association with other immunosuppressive factors (TAMs, FoxP3+ Tregs, IDO) was assessed from the results that were based on the same study material, which was published separately [ 24 , 25 ]. This study focused on CD8+ and GrB+ lymphocytes, because CD8 is a marker for all cytotoxic T cells and this marker does not correlate with lymphocyte activity.…”

Newly identified form of phenotypic plasticity of cancer: immunogenic mimicry

“…Recently, it was discovered that cancer cells can ectopically express CTLA4, in this case due to copy number gains (amplification) [67]. However, there may be other forms of immune escape mechanisms: a newly discovered one is the expression of the IDO1 enzyme producing kynurenin that induces T cell death [68][69][70]. Copy number variations (CNV) affecting CD40 and CD252 in cancers can also provide another novel excape mechanism [67,71].…”