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 APOBEC3A, 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 mutant (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 APOBEC3A, its DNA mutagenic activity and PD-L1-mediated antitumoral immunity. This work nominates APOBEC3A as a mechanism of immune evasion and a potential biomarker for the therapeutic efficacy of immune checkpoint blockade. Implications: APOBEC3A catalytic activity induces replication-associated DNA damage to promote PD-L1 expression implying that APOBEC3A-driven mutagenesis represents both a mechanism of tumor immune evasion and a therapeutically targetable vulnerability in cancer cells.

中文翻译：

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胞苷脱氨酶 APOBEC3A 以 JNK/c-JUN 依赖性方式调节癌细胞中 PD-L1 的表达

程序性死亡配体 1 (PD-L1) 通过与 PD-1 受体结合并抑制 T 细胞活性来促进肿瘤免疫逃避。虽然 PD-L1 表达的调节尚不完全清楚，但其表达与肿瘤突变负荷和对免疫检查点治疗的反应有关。在这里，我们报告载脂蛋白 B mRNA 编辑酶，催化多肽样 3A (APOBEC3A) 是 PD-L1 表达的重要调节剂。使用 APOBEC3A 诱导表达系统以及针对内源性 APOBEC3A 的 siRNA，我们发现 APOBEC3A 调节癌症中 PD-L1 mRNA 和蛋白质水平以及 PD-L1 细胞表面表达。机制上，APOBEC3A 诱导的 PD-L1 表达依赖于 APOBEC3A 催化活性，因为催化死亡的 APOBEC3A 突变体 (E72A) 未能诱导 PD-L1 表达。此外，APOBEC3A 诱导的 PD-L1 表达依赖于复制相关的 DNA 损伤和 JNK/c-JUN 信号，但不依赖于干扰素信号。此外，我们证实了这些发现在患者肿瘤中的相关性，因为 APOBEC3A 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 APOBEC3A、其 DNA 诱变活性和 PD-L1 介导的抗肿瘤免疫之间的新联系。这项工作将 APOBEC3A 提名为免疫逃避机制和免疫检查点阻断治疗效果的潜在生物标志物。影响：