title: Wnt5A regulates expression of tumor-associated antigens in melanoma via changes in signal transducers and activators of transcription 3 phosphorylation.
abstract: There are currently no effective therapies for metastatic melanoma and targeted immunotherapy results in the remission of only a very small percentage of tumors. In this study, we show that the noncanonical Wnt ligand, Wnt5A, can increase melanoma metastasis in vivo while down-regulating the expression of tumor-associated antigens important in eliciting CTL responses (e.g., MART-1, GP100, and tyrosinase). Melanosomal antigen expression is governed by MITF, PAX3, and SOX10 and is inhibited upon signal transducers and activators of transcription 3 (STAT3) activation, via decreases in PAX3 and subsequently MITF expression. Increasing Wnt5A in Wnt5A-low cells activated STAT3, and STAT3 was decreased upon Wnt5A knockdown. Downstream targets such as PAX3, MITF, and MART-1 were also affected by Wnt5A treatment or knockdown. Staining of a melanoma tissue array also highlighted the inverse relationship between MART-1 and Wnt5A expression. PKC activation by phorbol ester mimicked Wnt5A effects, and Wnt5A treatment in the presence of STAT3 or PKC inhibitors did not lower MART-1 levels. CTL activation studies showed that increases in Wnt5A correspond to decreased CTL activation and vice versa, suggesting that targeting Wnt5A before immunotherapy may lead to the enhancement of current targeted immunotherapy for patients with metastatic melanoma.
authors.affiliation: Laboratory of Immunology and the Research Resources Branch, Gerontology Research Center, National Institute on Aging, NIH, Baltimore, Maryland 21224, USA.
authors.forename: Samudra K
authors.initials: SK
authors.lastname: Dissanayake
authors.forename: Purevdorj B
authors.initials: PB
authors.lastname: Olkhanud
authors.forename: Michael P
authors.initials: MP
authors.lastname: O'Connell
authors.forename: Arnell
authors.initials: A
authors.lastname: Carter
authors.forename: Amanda D
authors.initials: AD
authors.lastname: French
authors.forename: Tura C
authors.initials: TC
authors.lastname: Camilli
authors.forename: Chineye D
authors.initials: CD
authors.lastname: Emeche
authors.forename: Kyle J
authors.initials: KJ
authors.lastname: Hewitt
authors.forename: Devin T
authors.initials: DT
authors.lastname: Rosenthal
authors.forename: Poloko D
authors.initials: PD
authors.lastname: Leotlela
authors.forename: Michael S
authors.initials: MS
authors.lastname: Wade
authors.forename: Sherry W
authors.initials: SW
authors.lastname: Yang
authors.forename: Larry
authors.initials: L
authors.lastname: Brant
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Nickoloff
authors.forename: Jane L
authors.initials: JL
authors.lastname: Messina
authors.forename: Arya
authors.initials: A
authors.lastname: Biragyn
authors.forename: Keith S
authors.initials: KS
authors.lastname: Hoek
authors.forename: Dennis D
authors.initials: DD
authors.lastname: Taub
authors.forename: Dan L
authors.initials: DL
authors.lastname: Longo
authors.forename: Vernon K
authors.initials: VK
authors.lastname: Sondak
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Hewitt
authors.forename: Ashani T
authors.initials: AT
authors.lastname: Weeraratna
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D008213:Lymphocyte Activation; D058965:MART-1 Antigen; D008545:Melanoma / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D008546:Melanoma, Experimental / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics; D010766:Phosphorylation; D034741:RNA, Small Interfering / Q000235:genetics; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D013601:T-Lymphocytes / Q000276:immunology; D014158:Transcription, Genetic; D014162:Transfection; D051153:Wnt Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D000071818:Wnt-5a Protein
chemical_list: D000951:Antigens, Neoplasm; D058965:MART-1 Antigen; C548667:MLANA protein, human; C548668:Mlana protein, mouse; D009363:Neoplasm Proteins; D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; C438615:Wnt5a protein, mouse