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.
MeSH terms
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Animals
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B7-H1 Antigen / genetics
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B7-H1 Antigen / immunology*
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Cell Line, Tumor
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Colorectal Neoplasms / genetics
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Colorectal Neoplasms / immunology*
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Colorectal Neoplasms / pathology
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Epithelial Cells / immunology
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Epithelial Cells / pathology
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Female
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Gene Expression Regulation, Neoplastic*
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Humans
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Intracellular Signaling Peptides and Proteins / genetics
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Intracellular Signaling Peptides and Proteins / immunology
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Lung Neoplasms / genetics
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Lung Neoplasms / immunology*
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Lung Neoplasms / pathology
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MAP Kinase Kinase Kinases / genetics
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MAP Kinase Kinase Kinases / immunology
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Male
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Mice
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Mice, Inbred BALB C
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Mice, Inbred C57BL
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Neoplasm Transplantation
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Protein Binding
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / immunology
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Proto-Oncogene Proteins p21(ras) / genetics
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Proto-Oncogene Proteins p21(ras) / immunology*
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RNA Cleavage
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RNA Stability
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RNA, Messenger / genetics
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RNA, Messenger / immunology
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Signal Transduction
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Tristetraprolin / genetics
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Tristetraprolin / immunology*
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Tumor Escape*
Substances
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B7-H1 Antigen
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Cd274 protein, mouse
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Intracellular Signaling Peptides and Proteins
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RNA, Messenger
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Tristetraprolin
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Zfp36 protein, mouse
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MAP-kinase-activated kinase 2
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Protein Serine-Threonine Kinases
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MAP Kinase Kinase Kinases
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Hras protein, mouse
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Proto-Oncogene Proteins p21(ras)