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YAP-Induced PD-L1 Expression Drives Immune Evasion in BRAFi-Resistant Melanoma

 Min Hwan Kim  ;  Chang Gon Kim  ;  Sang-Kyum Kim  ;  Sang Joon Shin  ;  Eun Ah Choe  ;  Su-Hyung Park  ;  Eui-Cheol Shin  ;  Joon Kim 
 CANCER IMMUNOLOGY RESEARCH, Vol.6(3) : 255-266, 2018 
Journal Title
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Activation of YAP, a Hippo pathway effector, is an important resistance mechanism to BRAF inhibitor (BRAFi) in melanoma. Emerging evidence also suggests that YAP is involved in suppression of the antitumor immune response. However, the potential direct impact of YAP activity on cytotoxic T-cell immune responses has not been explored yet. Here, we show that BRAFi-resistant melanoma cells evade CD8(+) T-cell immune responses in a PD-L1-dependent manner by activating YAP, which synchronously supports melanoma cell survival upon BRAF inhibition. PD-L1 expression is elevated in BRAFi-resistant melanoma cells, in which YAP is robustly activated, and YAP knockdown decreases PD-L1 expression. In addition, constitutively active YAP (YAP-5SA) increases PD-L1 expression by binding to an upstream enhancer of the PD-L1 gene and potentiating its transcription. Both BRAFi-resistant and YAP-5SA-expressing melanoma cells suppress the cytotoxic function and cytokine production of Melan-A-specific CD8(+) T cells, whereas anti-PD-1 antibody reverses the YAP-mediated T-cell suppression. Moreover, nuclear enrichment of YAP in clinical melanoma samples correlates with increased PD-L1 expression. Our findings show that YAP directly mediates evasion of cytotoxic T-cell immune responses in BRAFi-resistant melanoma cells by upregulating PD-L1, and targeting of YAP-mediated immune evasion may improve prognosis of melanoma patients. Cancer Immunol Res; 6(3); 1-12. (c)2018 AACR.
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1. College of Medicine (의과대학) > Dept. of Pathology (병리학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
Yonsei Authors
Kim, Sang Kyum(김상겸) ORCID logo https://orcid.org/0000-0003-0768-9923
Shin, Sang Joon(신상준) ORCID logo https://orcid.org/0000-0001-5350-7241
Choe, Eun Ah(최은아) ORCID logo https://orcid.org/0000-0001-7700-8711
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