[PDF][PDF] Oncogenic RAS signaling promotes tumor immunoresistance by stabilizing PD-L1 mRNA

MA Coelho, S de Carné Trécesson, S Rana, D Zecchin… - Immunity, 2017 - cell.com
MA Coelho, S de Carné Trécesson, S Rana, D Zecchin, C Moore, M Molina-Arcas, P East
Immunity, 2017cell.com
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 …
Summary
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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