Oncogenic RAS Signaling Promotes Tumor Immunoresistance by Stabilizing PD-L1 mRNA
- PMID: 29246442
- PMCID: PMC5746170
- DOI: 10.1016/j.immuni.2017.11.016
Oncogenic RAS Signaling Promotes Tumor Immunoresistance by Stabilizing PD-L1 mRNA
Abstract
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: KRAS; PD-L1; RAS; TTP; immunotherapy; tristetraprolin.
Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.
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Comment in
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RAS and PD-L1: A Masters' Liaison in Cancer Immune Evasion.Immunity. 2017 Dec 19;47(6):1007-1009. doi: 10.1016/j.immuni.2017.12.001. Immunity. 2017. PMID: 29262340
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