Journal
IMMUNITY
Volume 47, Issue 6, Pages 1083-+Publisher
CELL PRESS
DOI: 10.1016/j.immuni.2017.11.016
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Funding
- Francis Crick Institute - Cancer Research UK [FC001070]
- UK Medical Research Council [FC001070]
- Wellcome Trust [FC001070, 103799/Z/14/Z]
- European Research Council
- National Institute of Environmental Health Sciences, NIH
- European Commission Marie Sklodowska-Curie Actions programme, iGEMMdev
- Cancer Research UK [15680] Funding Source: researchfish
- Cancer Research UK
- Versus Arthritis [20265] Funding Source: researchfish
- The Francis Crick Institute [10074, 703228-IGEMMdev, 10002, 10011, 10009, 10071, 10070] Funding Source: researchfish
- Wellcome Trust [103799/A/14/Z] Funding Source: researchfish
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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.
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