演題

ミスマッチ修復機構欠損を有する大腸癌におけるmicroRNAによるPD-L1調整機構

[演者] 芦澤 舞:1
[著者] 岡山 洋和:1, Min Aung Kyi Thar:1,2, 野田 勝:2, 青砥 慶太:1, 中島 隆宏:1, 石亀 輝英:3, 円谷 彰:1, 丸橋 繁:3, 河野 浩二:1
1:福島県立医科大学 消化管外科, 2:福島県立医科大学 乳腺外科, 3:福島県立医科大学 肝胆膵・移植外科

PD-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). Upregulated expression of PD-1 on T-cells and PD-L1 on tumor cells delivers inhibitory signals to suppress T-cell activation, leading to immunosuppressive 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 immunosuppressive microenvironment by directly targeting PD-L1. Using miRNA expression profiles of 260 tumors obtained through The Cancer Genome Atlas (TCGA), 47 miRNA probes were found to be inversely correlated with PD-L1 expression. Among them, 19 mature miRNAs were downregulated in MMR-deficient tumors. Furthermore, eight in silico miRNA-target prediction programs were utilized to identify potential miRNAs, putative biding sites of which are present in the 3' untranslated region (UTR) of the PD-L1 mRNA. This led the identification of several tumor suppressive miRNAs as candidates for further analyses. CRC cell lines were transfected with miRNA mimics and inhibitors, and PD-L1 expression was examined by qRT-PCR, western blotting and flow cytometry. We found that forced expression of some of the candidate miRNAs could decrease PD-L1 expression on cancer cells, suggesting that PD-L1 expression is at least in part regulated by miRNAs. To determine if transfected miRNAs in cancer cells affect T-cell function via PD-L1 inhibition, we are currently planning to conduct the T-cell apoptosis assay in a co-culture model. Our findings may facilitate to understand the role of miRNAs in PD-L1 regulation and may also suggest the potential of miRNAs to serve as biomarkers and therapeutic target for cancer immunotherapy.
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