Cytidine Deaminase APOBEC3A Regulates PD-L1 Expression in Cancer Cells in a JNK/c-JUN-Dependent Manner.
Cytidine Deaminase APOBEC3A Regulates PD-L1 Expression in Cancer Cells in a JNK/c-JUN-Dependent Manner.
复制标题
DOI：
10.1158/1541-7786.mcr-21-0219
复制
发表时间：
2021-09
期刊：
影响因子：
--
通讯作者：
Morgan MA
中科院分区：
文献类型：
--
作者：
Zhao K;Zhang Q;Flanagan SA;Lang X;Jiang L;Parsels LA;Parsels JD;Zou W;Lawrence TS;Buisson R;Green MD;Morgan MA
程序性死亡配体1（PD-L1）通过接合PD-1受体和抑制T细胞活性来促进肿瘤免疫逃避。虽然PD-L1表达的调控尚未完全了解，但其表达与肿瘤突变负荷和对免疫检查点治疗的反应相关。在这里，我们报告载脂蛋白B mRNA编辑酶，催化多肽样3A（APOBEC 3A）是PD-L1表达的重要调节因子。使用APOBEC 3A诱导型表达系统以及针对内源性APOBECA的siRNA，我们发现APOBEC 3A调节癌症中PD-L1 mRNA和蛋白水平以及PD-L1细胞表面表达。从机制上讲，APOBEC 3A诱导的PD-L1表达依赖于APOBEC 3A催化活性，因为催化死亡的APOBEC 3A突变体（E72 A）无法诱导PD-L1表达。此外，APOBEC 3A诱导的PD-L1表达依赖于复制相关的DNA损伤和JNK/c-JUN信号传导，而不是干扰素信号传导。此外，我们证实了这些发现在患者肿瘤中的相关性，因为APOBEC 3A表达和突变特征与多种患者癌症类型中的PD-L1表达相关。这些数据提供了APOBECA、其DNA诱变活性和PD-L1介导的抗肿瘤免疫之间的新联系。这项工作提名APOBEC 3A作为免疫逃避的机制和免疫检查点阻断治疗效果的潜在生物标志物。
Programmed death-ligand 1 (PD-L1) promotes tumor immune evasion by engaging the PD-1 receptor and inhibiting T-cell activity. While the regulation of PD-L1 expression is not fully understood, its expression is associated with tumor mutational burden and response to immune checkpoint therapy. Here, we report that Apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like 3A (APOBEC3A) is an important regulator of PD-L1 expression. Using an APOBEC3A inducible expression system as well as siRNA against endogenous APOBECA, we found that APOBEC3A regulates PD-L1 mRNA and protein levels as well as PD-L1 cell surface expression in cancer. Mechanistically, APOBEC3A-induced PD-L1 expression was dependent on APOBEC3A catalytic activity as catalytically dead APOBEC3A mutants (E72A) failed to induce PD-L1 expression. Furthermore, APOBEC3A-induced PD-L1 expression was dependent on replication-associated DNA damage and JNK/c-JUN signaling but not interferon signaling. In addition, we confirmed the relevance of these finding in patient tumors as APOBEC3A expression and mutational signature correlated with PD-L1 expression in multiple patient cancer types. These data provide a novel link between APOBECA, its DNA mutagenic activity and PD-L1-mediated anti-tumoral immunity. This work nominates APOBEC3A as a mechanism of immune evasion and a potential biomarker for the therapeutic efficacy of immune checkpoint blockade.