内容紹介
Regulation of PD-L1 by MicroRNA in Mismatch Repair Deficient-Colorectal Cancer
Summary
Programmed cell death 1(PD-1)/PD-ligand 1(PD-L1)immune checkpoint blockade has emerged as a promising therapeutic strategy in various types of cancer. In a recent phase Ⅱ clinical trial, treatment with the anti-PD-1 agent, pembrolizumab, resulted in considerable clinical benefit in patients with mismatch repair(MMR)-deficient colorectal cancer(CRC). Upregulation of PD-1 on T-cells and PD-L1 on tumor cells induces inhibitory signals to suppress T-cell activation, leading to an immune-suppressive microenvironment particularly in MMR-deficient tumors. However, the regulation of PD-L1 expression on CRC cells is poorly understood. We hypothesized that certain microRNAs(miRNAs)are involved in the immunosuppressive microenvironment by directly targeting PD-L1. We identified candidate miRNAs by RNA-sequence analyses for mRNA and miRNA expression obtained from the TCGA colon adenocarcinoma database combined with miRNA target prediction programs. We found that forced miRNA expression could decrease PD-L1 expression on cancer cell lines. Our findings may facilitate an understanding of the role of miRNAs in PD-L1 regulation and also suggest potential miRNAs to serve as biomarkers and therapeutic targets for cancer immunotherapy.
要旨
ミスマッチ修復機構欠損(mismatch repair deficient: dMMR)を有する大腸癌において,programmed cell death 1(PD-1)/PD-ligand 1(PD-L1)シグナルを標的とした免疫チェックポイント阻害薬の有用性が期待されている。しかし大腸癌においてPD-1/PD-L1シグナルの制御機構は,十分に明らかにされていない。microRNA(miRNA)は,癌において重要な役割を担うことが知られ,腫瘍微小環境における免疫チェックポイント分子の調整にもかかわることが報告されてきている。われわれは,本研究にてdMMR大腸癌の免疫抑制的微小環境においてPD-L1発現を制御するmiRNAを特定することを目的とし,検証を行っている。
目次
Summary
Programmed cell death 1(PD-1)/PD-ligand 1(PD-L1)immune checkpoint blockade has emerged as a promising therapeutic strategy in various types of cancer. In a recent phase Ⅱ clinical trial, treatment with the anti-PD-1 agent, pembrolizumab, resulted in considerable clinical benefit in patients with mismatch repair(MMR)-deficient colorectal cancer(CRC). Upregulation of PD-1 on T-cells and PD-L1 on tumor cells induces inhibitory signals to suppress T-cell activation, leading to an immune-suppressive microenvironment particularly in MMR-deficient tumors. However, the regulation of PD-L1 expression on CRC cells is poorly understood. We hypothesized that certain microRNAs(miRNAs)are involved in the immunosuppressive microenvironment by directly targeting PD-L1. We identified candidate miRNAs by RNA-sequence analyses for mRNA and miRNA expression obtained from the TCGA colon adenocarcinoma database combined with miRNA target prediction programs. We found that forced miRNA expression could decrease PD-L1 expression on cancer cell lines. Our findings may facilitate an understanding of the role of miRNAs in PD-L1 regulation and also suggest potential miRNAs to serve as biomarkers and therapeutic targets for cancer immunotherapy.
要旨
ミスマッチ修復機構欠損(mismatch repair deficient: dMMR)を有する大腸癌において,programmed cell death 1(PD-1)/PD-ligand 1(PD-L1)シグナルを標的とした免疫チェックポイント阻害薬の有用性が期待されている。しかし大腸癌においてPD-1/PD-L1シグナルの制御機構は,十分に明らかにされていない。microRNA(miRNA)は,癌において重要な役割を担うことが知られ,腫瘍微小環境における免疫チェックポイント分子の調整にもかかわることが報告されてきている。われわれは,本研究にてdMMR大腸癌の免疫抑制的微小環境においてPD-L1発現を制御するmiRNAを特定することを目的とし,検証を行っている。