Oncogenic RAS signaling promotes tumor immunoresistance by stabilizing PD-L1 mRNA
Matthew A Coelho
Sophie De Carne Trecesson
Sareena Rana
Davide Zecchin
Christopher Moore
Miriam Molina-Arcas
Philip East
Bradley Spencer-Dene
Emma Nye
Karin Barnouin
Ambrosius P Snijders
Wi S Lai
Perry J Blackshear
Julian Downward
10779/crick.12563585.v1
https://crick.figshare.com/articles/journal_contribution/Oncogenic_RAS_signaling_promotes_tumor_immunoresistance_by_stabilizing_PD-L1_mRNA/12563585
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.
2020-06-26 09:46:45
KRAS
PD-L1
RAS
TTP
immunotherapy
tristetraprolin
Animals
B7-H1 Antigen
Cell Line, Tumor
Colorectal Neoplasms
Epithelial Cells
Female
Gene Expression Regulation, Neoplastic
Humans
Intracellular Signaling Peptides and Proteins
Lung Neoplasms
MAP Kinase Kinase Kinases
Male
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Neoplasm Transplantation
Protein Binding
Protein-Serine-Threonine Kinases
Proto-Oncogene Proteins p21(ras)
RNA Cleavage
RNA Stability
RNA, Messenger
Signal Transduction
Tristetraprolin
Tumor Escape
Downward FC001070
CB
HP
PRT
FC-ack
GEP-ack
CS-ack
1107 Immunology
Immunology