Abstract
BackgroundMycosis fungoides (MF) is a primary cutaneous T-cell lymphoma (CTCL) that transforms from mature, skin-homing T cells and progresses during the early stages in the skin. The role of the skin microenvironment in MF development is unclear, but recent findings in a variety of cancers have highlighted the role of stromal fibroblasts in promoting or inhibiting tumorigenesis. Stromal fibroblasts are an important part of the cutaneous tumor microenvironment (TME) in MF. Here we describe studies into the interaction of TME-fibroblasts and malignant T cells to gain insight into their role in CTCL.MethodsSkin from normal (n = 3) and MF patients (n = 3) were analyzed for FAPα by immunohistochemistry. MyLa is a CTCL cell line that retains expression of biomarkers TWIST1 and TOX that are frequently detected in CTCL patients. MyLa cells were cultured in the presence or absence of normal or MF skin derived fibroblasts for 5 days, trypsinized to detached MyLa cells, and gene expression analyzed by RT-PCR for MF biomarkers (TWIST1 and TOX), Th1 markers (IFNG, TBX21), Th2 markers (GATA3, IL16), and proliferation marker (MKI67). Purified fibroblasts were assayed for VIM and ACTA2 gene expression. Cellular senescence assay was performed to assess senescence.ResultsMF skin fibroblast showed increased expression of FAP-α with increasing stage compared to normal. Normal fibroblasts co-cultured with MyLa cells suppressed expression of TWIST1 (p < 0.0006), and TOX (p < 0.03), GATA3 (p < 0.02) and IL16 (p < 0.03), and increased expression of IFNG (p < 0.03) and TBX21 (p < 0.03) in MyLa cells. In contrast, MyLa cells cultured with MF fibroblasts retained high expression of TWIST1, TOX and GATA3. MF fibroblasts co-culture with MyLa cells increased expression of IL16 (p < 0.01) and IL4 (p < 0.02), and suppressed IFNG and TBX21 in MyLa cells. Furthermore, expression of MKI67 in MyLa cells was suppressed by normal fibroblasts compared to MF fibroblasts.ConclusionSkin fibroblasts represent important components of the TME in MF. In co-culture model, normal and MF fibroblasts have differential influence on T-cell phenotype in modulating expression of Th1 cytokine and CTCL biomarker genes to reveal distinct roles with implications in MF progression.
Highlights
Mycosis fungoides (MF) is a primary cutaneous T-cell lymphoma (CTCL) that transforms from mature, skin-homing T cells and progresses during the early stages in the skin
Normal fibroblasts alter expression of CTCL biomarkers in CTCL cells Expression of TWIST1 and TOX is frequently increased in tumor T cells from CTCL patients [42, 43]
Of the three cell lines analyzed, only MyLa cells expressed these CTCL biomarker genes (Fig. 3d), indicating that abnormal gene expression similar to that seen in patient-derived T cells is preserved MyLa cells
Summary
Mycosis fungoides (MF) is a primary cutaneous T-cell lymphoma (CTCL) that transforms from mature, skin-homing T cells and progresses during the early stages in the skin. Stromal fibroblasts are an important part of the cutaneous tumor microenvironment (TME) in MF. Skin histology of early patch MF lesions show a low tumor burden with T cell infiltration characterized by Th1 cytokine bias, with increased expression of IL-2 and IFN-γ [3,4,5,6]. Th1 chemokines such as CXC chemokine ligand 9 (CXCL 9) and CXCL10 are expressed in lesional skin of early CTCL, when epidermotropism of tumor cells is evident [7]. Gene expression changes in SS, such as decreased expression of IFN-γ, and increased expression of unique biomarker genes identified in SS such as TWIST1, and TOX are frequent and represent important features of CTCL [13,14,15]
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