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Molecular targets for therapy

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

Leukemia volume 31, pages 2780–2790 (2017)Cite this article

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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.

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Acknowledgements

Research was supported by NIDDK P30DK046200. AJ, EA and FJS were supported by a grant from the Ludwig Center at Harvard. This study was funded, in part, by a Chief Academic Officer (CAO) Pilot Grant (2015) awarded to FS and DA.

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Author notes

  1. A R Pyzer and D Stroopinsky: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Medicine, Beth Israel Deaconess Medical Center, Hematology/Oncology, Harvard Medical School, Boston, MA, USA

    A R Pyzer, D Stroopinsky, J Rosenblatt, A Washington, M Coll, L Cole, K Palmer, A Ephraim, R K Leaf, M Nahas, A Apel, M Bar-Natan, S Jain, M McMasters, L Mendez, J Arnason & D Avigan

  2. Department of Pathology, Department of Pathology, Institute for RNA Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA

    E Anastasiadou, A L Jiao & F Slack

  3. Department of Medical Oncology, Dana Farber Cancer Institute, Medical Oncology, Harvard Medical School, Boston, MA, USA

    H Rajabi, A Tagde & D Kufe

  4. Department of Internal Medicine, Section of Pulmonary, Critical Care and Sleep Medicine, Yale University School of Medicine, New Haven, CT, USA

    J-H Chu

  5. Division of Endocrinology, Department of Medicine, Diabetes and Metabolism, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA

    L T Tsai & D E Tenen

  6. Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA

    B A Raby

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  1. A R Pyzer
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Correspondence to D Stroopinsky.

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DK holds equity in Genus Oncology and is a consultant to the company. The remaining authors declare no conflict of interest.

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Pyzer, A., Stroopinsky, D., Rosenblatt, J. et al. MUC1 inhibition leads to decrease in PD-L1 levels via upregulation of miRNAs. Leukemia 31, 2780–2790 (2017). https://doi.org/10.1038/leu.2017.163

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