Immunity
Volume 47, Issue 6, 19 December 2017, Pages 1083-1099.e6
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Article
Oncogenic RAS Signaling Promotes Tumor Immunoresistance by Stabilizing PD-L1 mRNA

https://doi.org/10.1016/j.immuni.2017.11.016Get rights and content
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Highlights

  • Oncogenic RAS signaling via MEK increases PD-L1 expression

  • RAS regulates PD-L1 through AU-rich elements (AREs) in the 3′ UTR of PD-L1 mRNA

  • The ARE-binding protein tristetraprolin (TTP) negatively regulates PD-L1 expression

  • Restoration of tumor cell TTP activity enhances anti-tumor immunity

Summary

The immunosuppressive protein PD-L1 is upregulated in many cancers and contributes to evasion of the host immune system. The relative importance of the tumor microenvironment and cancer cell-intrinsic signaling in the regulation of PD-L1 expression remains unclear. We report that oncogenic RAS signaling can upregulate tumor cell PD-L1 expression through a mechanism involving increases in PD-L1 mRNA stability via modulation of the AU-rich element-binding protein tristetraprolin (TTP). TTP negatively regulates PD-L1 expression through AU-rich elements in the 3′ UTR of PD-L1 mRNA. MEK signaling downstream of RAS leads to phosphorylation and inhibition of TTP by the kinase MK2. In human lung and colorectal tumors, RAS pathway activation is associated with elevated PD-L1 expression. In vivo, restoration of TTP expression enhances anti-tumor immunity dependent on degradation of PD-L1 mRNA. We demonstrate that RAS can drive cell-intrinsic PD-L1 expression, thus presenting therapeutic opportunities to reverse the innately immunoresistant phenotype of RAS mutant cancers.

Keywords

RAS
KRAS
immunotherapy
tristetraprolin
TTP
PD-L1

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