miRNA-148a-3p Regulates Immunosuppression in DNA Mismatch Repair–Deficient Colorectal Cancer by Targeting PD-L1

Abstract

Immunotherapy against the interaction between programmed cell death 1/programmed cell death ligand 1 (PD-L1) has emerged as a promising strategy for colorectal cancer with mismatch repair deficiency (dMMR) or microsatellite instability-high (MSI-H). The study aimed to identify miRNAs that posttranscriptionally control PD-L1 expression on tumor cells and also regulate immune evasion. A comprehensive miRNA screening using The Cancer Genome Atlas (TCGA) dataset (n ¼ 260) combined with eight different miRNA target prediction programs resulted in the identification of a tumor suppressive miRNA, miR-148a-3p, as a potential negative regulator of PD-L1 expression, particularly in dMMR/MSI-H colorectal cancer. Using multiple cohorts of colorectal cancer, including TCGA data, a microarray dataset (n ¼ 148), and formalin-fixed, paraffin-embedded samples (n ¼ 395), we found that the expression of miR-148a-3p was decreased in dMMR/MSI-H tumors, correlating inversely with PD-L1 levels. We demonstrate that miR-148a-3p directly binds to the 3 0 -untranslated region of PD-L1, thereby reducing whole-cell and cell surface PD-L1 levels in HCT116 and SW837 cell lines. Overexpression of miR-148a-3p repressed IFNg-induced PD-L1 expression on tumor cells and consequently diminished T-cell apoptosis in a coculture model of IL2-activated T cells and IFNg-treated tumor cells. In conclusion, our data support a regulatory mechanism of PD-L1 expression on tumor cells and immune suppression via miR-148a-3p downregulation in colorectal cancer. Implications:This study provides novel evidence that miR-148a-3p negatively regulates tumor cell PD-L1 expression and decreased levels of miR-148a-3p contributes to the immunosuppressive tumor microenvironment.

Novel Multiple miRNA-Based Signatures for Predicting Overall Survival and Recurrence-Free Survival of Colorectal Cancer Patients

“…Hibino et al [26] found that miR-148a could promote the invasion of CRC through MMP7. Ashizawa et al [27] revealed that miR-148a-3p could negatively regulate the expression of PD-L1 in colorectal cancer cells, and further the immunosuppressive tumor microenvironment. Zhuang et al [28] demonstrated that miR-106b-5p is a suppressor of CRC through the MALAT1/miR-106b-5p/SLAIN2 signaling pathway.…”

The role of cancer-derived microRNAs in cancer immune escape

“…Increased immune checkpoint ligands especially PD-L1 is closely related with cancerassociated miRNA expression pattern. To be more specific, previous studies have indicated that the loss of miR-3609, miR-195-5p, miR-148a-3p, miR-873, miRNA-497-5p, miR-191-5p, miR-34a, and miR-138 closely correlated with the increased PD-L1 expression on numerous cancer cells [86][87][88][89][90][91][92][93][94]. In addition, Dong et al found that decreased miR-140, miR-142, miR-340, and miR-383 enormously elevated PD-L1 expression on cervical cancer cells [95].…”

PD/1-PD-Ls Checkpoint: Insight on the Potential Role of NK Cells

“…In this context, it has been recently shown that the hsa-miR-146a-5p may negatively regulate the surface expression of certain KIRs by mimicking a “missing self” condition and, as a consequence, by improving the NK cell mediated cytotoxicity (74). Moreover, recent studies have provided novel evidence that miR-148a-3p and miR-873 negatively regulate tumor cell PD-L1 expression (75, 76). Thus, these regulatory miRNA/targets axes might serve as an additional tool in tumor therapy.…”