title: Foxp3 expression in melanoma cells as a possible mechanism of resistance to immune destruction.
abstract: The forkhead transcription factor Foxp3 is the only definitive marker of CD4(+)CD25(+) regulatory T cells (Tregs) and has been identified as a key regulator in the development and function of Tregs. Foxp3 expression has been reported in a variety of solid tumors, including melanoma. In this study, we validated Foxp3 expression in both tumor-infiltrating Tregs and melanoma cells by performing immunohistochemical analysis of human melanoma tissue sections. Further, we assessed Foxp3 expression in melanoma cell lines by performing flow cytometry, confocal microscopic analysis, reverse transcription-polymerase chain reaction (RT-PCR), and Western blotting. Inhibition of Foxp3 expression in melanoma cells using small interfering RNA (siRNA) resulted in downregulation of B7-H1 and transforming growth factor (TGF)-β expression; in contrast, Foxp3 overexpression resulted in the upregulation of the expression of these proteins. Coculture of Foxp3-expressing melanoma cells with naive CD4(+)CD25(-) T cells resulted in strong inhibition of T-cell proliferation. This antiproliferative effect was partially abrogated by specific inhibition of Foxp3 expression and was effectively enhanced by overexpression of Foxp3. We observed an attenuated antiproliferative effect even when melanoma cells and T cells in the coculture were separated using Transwell inserts. These findings indicated that melanoma cells could have Foxp3-dependent Treg-like suppressive effects on T cells and suggested that the mimicking of Treg function by melanoma cells may represent a possible mechanism of tumor resistance to immune destruction in the melanoma tumor microenvironment.
authors.affiliation: Department of Dermatology, Xijing Hospital, Fourth Military Medical University, 710032 Xi'an, China.
authors.forename: Junzhou
authors.initials: J
authors.lastname: Niu
authors.forename: Changli
authors.initials: C
authors.lastname: Jiang
authors.forename: Chunying
authors.initials: C
authors.lastname: Li
authors.forename: Ling
authors.initials: L
authors.lastname: Liu
authors.forename: Kai
authors.initials: K
authors.lastname: Li
authors.forename: Zhe
authors.initials: Z
authors.lastname: Jian
authors.forename: Tianwen
authors.initials: T
authors.lastname: Gao
mesh_terms: D015703:Antigens, CD / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D060890:B7-H1 Antigen; D015704:CD4 Antigens / Q000096:biosynthesis; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018920:Coculture Techniques; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D053645:Interleukin-2 Receptor alpha Subunit / Q000096:biosynthesis; D008545:Melanoma / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D034741:RNA, Small Interfering / Q000235:genetics; D012878:Skin Neoplasms / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D019076:Transgenes / Q000235:genetics; D019139:Tumor Escape
chemical_list: D015703:Antigens, CD; D060890:B7-H1 Antigen; C423236:CD274 protein, human; D015704:CD4 Antigens; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D053645:Interleukin-2 Receptor alpha Subunit; D034741:RNA, Small Interfering; D016212:Transforming Growth Factor beta