MUC1 inhibition leads to decrease in PD-L1 levels via upregulation of miRNAs

Abstract

The PD-L1/PD-1 pathway is a critical component of the immunosuppressive tumor microenvironment in acute myeloid leukemia (AML), but little is known about its regulation. We investigated the role of the MUC1 oncoprotein in modulating PD-L1 expression in AML. Silencing of MUC1 in AML cell lines suppressed PD-L1 expression without a decrease in PD-L1 mRNA levels, suggesting a post-transcriptional mechanism of regulation. We identified the microRNAs miR-200c and miR-34a as key regulators of PD-L1 expression in AML. Silencing of MUC1 in AML cells led to a marked increase in miR-200c and miR-34a levels, without changes in precursor microRNA, suggesting that MUC1 might regulate microRNA-processing. MUC1 signaling decreased the expression of the microRNA-processing protein DICER, via the suppression of c-Jun activity. NanoString (Seattle, WA, USA) array of MUC1-silenced AML cells demonstrated an increase in the majority of probed microRNAs. In an immunocompetent murine AML model, targeting of MUC1 led to a significant increase in leukemia-specific T cells. In concert, targeting MUC1 signaling in human AML cells resulted in enhanced sensitivity to T-cell-mediated lysis. These findings suggest MUC1 is a critical regulator of PD-L1 expression via its effects on microRNA levels and represents a potential therapeutic target to enhance anti-tumor immunity.

Tumor-Intrinsic PD-L1 Signaling in Cancer Initiation, Development and Treatment: Beyond Immune Evasion

“…MUC1 elevates PD-L1 transcription by recruitment of MYC and NF-κB (a downstream effector of PI3K/AKT pathway ( 53 ) to the PD-L1 promoter in breast cancer ( 54 ). Also, MUC1 was shown to increase PD-L1 levels via downregulation of miR-34a and miR-200c, two direct suppressors of PD-L1 ( 55 – 57 ).…”

New Agents in the Treatment of Acute Myeloid Leukemia

“…Lenfoid malignitelerin ve solid tümörlerin tedavisinde kullanılmakta olan PD1/PD-L1 inhibitörleri (nivolumab, ipilimumab) ile yapılan preklinik çalışmalarda, bu ilaçların AML'de kullanılabileceği öngörülmüştür (44,45). Allojenik kök hücre nakli sonrası nüks olan hastalarda ipilimumab kullanımında immün-aracılı yan etkiler ve graft versus host hastalığı, tedavi kesilmesini gerektirecek ciddi yan etkiler arasında görülmüştür (46).…”

MicroRNAs as New Biomarkers for Diagnosis and Prognosis, and as Potential Therapeutic Targets in Acute Myeloid Leukemia

“…To summarized these concepts, we have illustrated in Table 2 the most important miRNAs found to play a role in AML, specifying for each miRNA the altered expression (up or downregulation), the mechanisms of dysregulation, their targets, and their functional effects in AML pathogenesis [ 23 , 28 , 31 , 32 , 33 , 41 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 , 90 , 91 , 92 , 93 , 94 , 95 , 96 , 97 , 98 , 99 , 100 , 101 , 102 , 103 , …”