内容紹介
Regulatory Mechanisms of PD-L1 Expression and Its Role in Immune Evasion
Summary
Immune checkpoint blockade therapy using anti-PD-1 or anti-PD-L1 antibodies can unleash anti-tumor immunity and induce durable remission in a variety of human cancers. However, the regulatory mechanisms of PD-L1 expression mediating immune evasion of cancer cells have not been fully elucidated, including the genetic alterations causing PD-L1 overexpression. Recently, we have reported a novel genetic mechanism of immune evasion associated with structural variations(SVs)disrupting the 3′-untranslated region(UTR)of the PD-L1 gene in various malignancies, such as aggressive lymphomas and gastrointestinal cancers. Despite a heterogenous nature of these SVs, they are closely associated with a marked upregulation of PD-L1 expression, which augments tumor growth and escape from anti-tumor immunity. Here we present an overview of the regulatory mechanisms of PD-L1 expression in cancer cells, highlighting the genetic mechanisms of PD-L1 constitutive activation, with specific focus on PD-L1 3′-UTR disruption.
要旨
近年,抗PD-1/PD-L1抗体が様々ながん腫に対して有効であることが示されて,がん免疫療法が脚光を浴びている。しかし未だにがん細胞が免疫を回避するために主要な役割を果たすPD-L1の発現制御メカニズムの理解は不十分であり,特にその遺伝学的機構については不明な点が多かった。最近,著者らはPD-L1の3′-UTR異常が様々ながん腫に存在し,免疫回避を引き起こすことを明らかにした。本稿では,PD-L1 3′-UTR異常を中心として,悪性腫瘍におけるPD-L1高発現をもたらすメカニズムについて概説する。
目次
Summary
Immune checkpoint blockade therapy using anti-PD-1 or anti-PD-L1 antibodies can unleash anti-tumor immunity and induce durable remission in a variety of human cancers. However, the regulatory mechanisms of PD-L1 expression mediating immune evasion of cancer cells have not been fully elucidated, including the genetic alterations causing PD-L1 overexpression. Recently, we have reported a novel genetic mechanism of immune evasion associated with structural variations(SVs)disrupting the 3′-untranslated region(UTR)of the PD-L1 gene in various malignancies, such as aggressive lymphomas and gastrointestinal cancers. Despite a heterogenous nature of these SVs, they are closely associated with a marked upregulation of PD-L1 expression, which augments tumor growth and escape from anti-tumor immunity. Here we present an overview of the regulatory mechanisms of PD-L1 expression in cancer cells, highlighting the genetic mechanisms of PD-L1 constitutive activation, with specific focus on PD-L1 3′-UTR disruption.
要旨
近年,抗PD-1/PD-L1抗体が様々ながん腫に対して有効であることが示されて,がん免疫療法が脚光を浴びている。しかし未だにがん細胞が免疫を回避するために主要な役割を果たすPD-L1の発現制御メカニズムの理解は不十分であり,特にその遺伝学的機構については不明な点が多かった。最近,著者らはPD-L1の3′-UTR異常が様々ながん腫に存在し,免疫回避を引き起こすことを明らかにした。本稿では,PD-L1 3′-UTR異常を中心として,悪性腫瘍におけるPD-L1高発現をもたらすメカニズムについて概説する。