Oncogenic RAS Signaling Promotes Tumor Immunoresistance by Stabilizing PD-L1 mRNA.
Loading...
ICR Authors
Authors
Coelho, MA
de Carné Trécesson, S
Rana, S
Zecchin, D
Moore, C
Molina-Arcas, M
East, P
Spencer-Dene, B
Nye, E
Barnouin, K
Snijders, AP
Lai, WS
Blackshear, PJ
Downward, J
de Carné Trécesson, S
Rana, S
Zecchin, D
Moore, C
Molina-Arcas, M
East, P
Spencer-Dene, B
Nye, E
Barnouin, K
Snijders, AP
Lai, WS
Blackshear, PJ
Downward, J
Document Type
Journal Article
Date
2017-12-12
Date Accepted
2017-11-20
Date Available
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.
Citation
Immunity, 2017, 47 (6), pp. 1083 - 1099.e6
Source Title
Publisher
ISSN
1074-7613
eISSN
1097-4180
Collections
Research Team
Lung Cancer Group