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.

免疫抑制蛋白 PD-L1 在许多癌症中表达上调，有助于逃避宿主免疫系统。肿瘤微环境和癌细胞内在信号传导在 PD-L1 表达调节中的相对重要性仍不清楚。我们报告，致癌 RAS 信号传导可以通过一种机制上调肿瘤细胞 PD-L1 表达，该机制涉及通过调节富含 AU 元件的结合蛋白 tristetraprolin (TTP) 来增加 PD-L1 mRNA 稳定性。 TTP 通过 PD-L1 mRNA 3' UTR 中富含 AU 的元件负向调节 PD-L1 表达。 RAS 下游的 MEK 信号传导导致激酶 MK2 磷酸化并抑制 TTP。在人类肺癌和结直肠肿瘤中，RAS 通路激活与 PD-L1 表达升高相关。在体内，TTP 表达的恢复可增强依赖于 PD-L1 mRNA 降解的抗肿瘤免疫。我们证明 RAS 可以驱动细胞内在的 PD-L1 表达，从而为逆转RAS突变癌症的先天免疫抵抗表型提供了治疗机会。