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.
Subject(s)
B7-H1 Antigen/genetics , Gene Expression Regulation, Leukemic , MicroRNAs/genetics , Mucin-1/metabolism , Animals , B7-H1 Antigen/metabolism , Cell Line, Tumor , Humans , Immunomodulation/genetics , Mice , Mucin-1/genetics , Proto-Oncogene Proteins c-jun/genetics , Proto-Oncogene Proteins c-jun/metabolism , Ribonuclease III/genetics , Ribonuclease III/metabolism , Transcriptional Activation , Up-RegulationABSTRACT
BACKGROUND: Endonasal dacryocystorhinostomy has recently become an important alternative to the classical external Toti procedure. OBJECTIVE: To analyse the outcome after endonasal dacryocystorhinostomy. METHODS: For this purpose 28 of 34 patients treated by endonasal dacryocystorhinostomy between May 1994 and November 1998 were investigated. RESULTS: After an average follow-up of 28 months, 23 of the 28 patients (82%) are free of symptoms. Two additional patients became symptom-free after revision surgery. The total success rate is 89%. The only complications seen were 2 cases of asymptomatic synechiae and one case of mild hyposmia. CONCLUSIONS: Endonasal dacryocystorhinostomy is a rapid, safe, and elegant method for the treatment of post-saccal nasolacrimal duct obstructions.
