第72回日本消化器外科学会総会 My Schedule

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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