内容紹介
Summary
Although immune checkpoint blockade therapy using anti-PD-1/PD-L1 antibodies can induce durable remission in a variety of human malignancies, the mechanisms regulating the expression of PD-1 ligands(PD-L1 and PD-L2)have not been fully investigated. Recently, we newly identified structural variations(SVs)disrupting the 3′-untranslated region(UTR)of the PD-L1/PD-L2 genes in various cancers, which caused a marked upregulation of these molecules and mediated immune escape of tumor cells. Particularly, these alterations were frequently observed in virus-related lymphomas, such as adult T-cell leukemia/lymphoma as well as Epstein-Barr virus-positive diffuse large B-cell lymphoma and extranodal NK/T-cell lymphoma. These results suggest a pivotal role of PD-L1/PD-L2-mediated immune evasion in the pathogenesis of virus-related tumors. Here we summarize the genetic alterations involving the PD-L1/PD-L2 genes in human cancers, highlighting their relevance in virus-associated tumors.
要旨
近年,免疫チェックポイント阻害剤が様々な悪性腫瘍に対して有効であることが示されており,がん免疫療法がたいへんな注目を集めている。これまでは,がん細胞が免疫を回避する際に重要な役割を果たすPD-L1やPD-L2の発現制御機構の理解は不十分であったが,最近遺伝子異常によりこれらの分子の恒常的活性化が引き起こされることが明らかとなってきた。本稿では,著者らが同定したPD-L1/PD-L2 3′-UTR異常を中心として,悪性腫瘍におけるPD-L1/PD-L2高発現をもたらす遺伝学的メカニズムについて概説する。さらに,これらの遺伝子異常とウイルス感染との関係やその臨床的意義について述べる。
目次
Although immune checkpoint blockade therapy using anti-PD-1/PD-L1 antibodies can induce durable remission in a variety of human malignancies, the mechanisms regulating the expression of PD-1 ligands(PD-L1 and PD-L2)have not been fully investigated. Recently, we newly identified structural variations(SVs)disrupting the 3′-untranslated region(UTR)of the PD-L1/PD-L2 genes in various cancers, which caused a marked upregulation of these molecules and mediated immune escape of tumor cells. Particularly, these alterations were frequently observed in virus-related lymphomas, such as adult T-cell leukemia/lymphoma as well as Epstein-Barr virus-positive diffuse large B-cell lymphoma and extranodal NK/T-cell lymphoma. These results suggest a pivotal role of PD-L1/PD-L2-mediated immune evasion in the pathogenesis of virus-related tumors. Here we summarize the genetic alterations involving the PD-L1/PD-L2 genes in human cancers, highlighting their relevance in virus-associated tumors.
要旨
近年,免疫チェックポイント阻害剤が様々な悪性腫瘍に対して有効であることが示されており,がん免疫療法がたいへんな注目を集めている。これまでは,がん細胞が免疫を回避する際に重要な役割を果たすPD-L1やPD-L2の発現制御機構の理解は不十分であったが,最近遺伝子異常によりこれらの分子の恒常的活性化が引き起こされることが明らかとなってきた。本稿では,著者らが同定したPD-L1/PD-L2 3′-UTR異常を中心として,悪性腫瘍におけるPD-L1/PD-L2高発現をもたらす遺伝学的メカニズムについて概説する。さらに,これらの遺伝子異常とウイルス感染との関係やその臨床的意義について述べる。