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