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インターロイキン-1βによる非小細胞肺癌におけるPD-L1発現制御機構の解析

平山, 藍子 HIRAYAMA, Aiko ヒラヤマ, アイコ 九州大学

2023.09.25

概要

九州大学学術情報リポジトリ
Kyushu University Institutional Repository

Regulation of PD-L1 expression in non–small
cell lung cancer by interleukin-1β
平山, 藍子

https://hdl.handle.net/2324/7157307
出版情報:Kyushu University, 2023, 博士(医学), 課程博士
バージョン:
権利関係:Creative Commons Attribution 4.0 International

氏 名:

平山 藍子

論文名:

Regulation of PD-L1 expression in non–small cell lung cancer by
interleukin-1β
(インターロイキン-1βによる非小細胞肺癌におけるPD-L1発現制御機構の解析)

区 分:



論 文 内 容 の 要 旨

背景: 免疫チェックポイント分子Programmed cell death-ligand 1 (PD-L1) は様々な癌腫の多様な細
胞に発現し、T細胞に発現するPD-1のリガンドとして働き免疫寛容を誘導する。進行期非小細胞肺癌に
おいては、癌細胞に発現するPD-L1が抗PD-1抗体、抗PD-L1抗体療法による臨床効果を予測するバイオ
マーカーとして用いられている。しかしながら、癌細胞上のPD-L1発現におけるサイトカインの詳細な
分子制御機構は明らかでない。
方法: 公開データベース解析による26種のサイトカインとPD-L1遺伝子発現の相関、並びに、singlecell RNA Sequence (scRNA-seq) による、非小細胞肺癌組織におけるサイトカイン遺伝子発現の網羅
的な検索を行った。その結果、我々は、interleukin-1β (IL-1β) を同定し、in vitro でIL-1βに
よるPD-L1発現制御機構の解析を行った。
結果: データベース解析により、9種類のサイトカインがPD-L1発現と有意な正の相関を示した。
scRNA-seqのデータ解析により、マクロファージが発現するIL-1βは腫瘍微小環境に豊富に存在し、腫
瘍の進行とともに発現量が増加していた。IL-1β単独刺激により非小細胞肺癌細胞のPD-L1発現は穏や
かに増加し、T細胞による細胞傷害活性を抑制した。IL-1βとPD-L1発現を正に制御することが知られ
るinterferon-γ (IFN-γ)の併用刺激は、それぞれの単独刺激よりも非小細胞肺癌細胞のPD-L1発現を
強く誘導した。IL-1β/IFN-γ併用刺激は、それぞれの単独刺激よりもmitogen-activated protein
kinase (MAPK) であるextracellular signal–regulated kinase1/2 (ERK1/2) のリン酸化とinterferon
regulatory factor 1 (IRF1) の核内発現を強く誘導し、転写因子IRF1及びc-FosのPD-L1遺伝子プロ
モーター領域への結合を増強させた。MAPKシグナルの特異的な阻害剤はIL-1β/IFN-γ併用刺激による
PD-L1発現を抑制し、このPD-L1発現はIL-1β-MAPK経路に依存的であることが示唆された。
結論: 我々の研究成果は、腫瘍微小環境に豊富に存在するIL-1βがIFN-γと協働し、MAPKシグナルの
活性化を介して癌細胞上のPD-L1発現が増強することを明らかにした。PD-L1を介した抗腫瘍免疫抑制
克服のためにIL-1β-MAPK経路を標的とした治療戦略が有望であることが示唆された。

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