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Immunity. 2017 Dec 19;47(6):1083-1099.e6. doi: 10.1016/j.immuni.2017.11.016. Epub 2017 Dec 12.

Oncogenic RAS Signaling Promotes Tumor Immunoresistance by Stabilizing PD-L1 mRNA.

Author information

1
Oncogene Biology, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK.
2
Lung Cancer Group, Division of Molecular Pathology, The Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK.
3
Computational Biology, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK.
4
Experimental Histopathology, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK.
5
Protein Analysis and Proteomics Laboratories, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK.
6
Signal Transduction Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.
7
Signal Transduction Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA; Departments of Medicine and Biochemistry, Duke University Medical Center, Durham, NC 27703, USA.
8
Oncogene Biology, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK; Lung Cancer Group, Division of Molecular Pathology, The Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK. Electronic address: julian.downward@crick.ac.uk.

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

PMID:
29246442
PMCID:
PMC5746170
DOI:
10.1016/j.immuni.2017.11.016
[Indexed for MEDLINE]
Free PMC Article

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