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

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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. (C) 2018 AACR.
Publisher
AMER ASSOC CANCER RESEARCH
Issue Date
2018-03
Language
English
Article Type
Article
Citation

CANCER IMMUNOLOGY RESEARCH, v.6, no.3, pp.255 - 266

ISSN
2326-6066
DOI
10.1158/2326-6066.CIR-17-0320
URI
http://hdl.handle.net/10203/241207
Appears in Collection
MSE-Journal Papers(저널논문)
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