Wnt5A regulates expression of tumor-associated antigens in melanoma via changes in signal transducers and activators of transcription 3 phosphorylation.
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.
Dissanayake
Samudra K
SK
Laboratory of Immunology and the Research Resources Branch, Gerontology Research Center, National Institute on Aging, NIH, Baltimore, Maryland 21224, USA.
Olkhanud
Purevdorj B
PB
O'Connell
Michael P
MP
Carter
Arnell
A
French
Amanda D
AD
Camilli
Tura C
TC
Emeche
Chineye D
CD
Hewitt
Kyle J
KJ
Rosenthal
Devin T
DT
Leotlela
Poloko D
PD
Wade
Michael S
MS
Yang
Sherry W
SW
Brant
Larry
L
Nickoloff
Brian J
BJ
Messina
Jane L
JL
Biragyn
Arya
A
Hoek
Keith S
KS
Taub
Dennis D
DD
Longo
Dan L
DL
Sondak
Vernon K
VK
Hewitt
Stephen M
SM
Weeraratna
Ashani T
AT
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
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