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MicroRNA Regulation of T-Cell Exhaustion in Cutaneous T Cell Lymphoma

  • Zhen Han
    Affiliations
    Division of Dermatology, Department of Surgery, City of Hope National Medical Center, Duarte, California, USA

    Beckman Research Institute, City of Hope National Medical Center, Duarte, California, USA
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  • Renee J. Estephan
    Affiliations
    Irell and Manella Graduate School of Biological Sciences, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, USA
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  • Xiwei Wu
    Affiliations
    Beckman Research Institute, City of Hope National Medical Center, Duarte, California, USA

    Department of Integrative Genomics, City of Hope National Medical Center, Duarte, California, USA
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  • Chingyu Su
    Affiliations
    Division of Dermatology, Department of Surgery, City of Hope National Medical Center, Duarte, California, USA

    Beckman Research Institute, City of Hope National Medical Center, Duarte, California, USA
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  • Yate-Ching Yuan
    Affiliations
    Beckman Research Institute, City of Hope National Medical Center, Duarte, California, USA

    Division of Translational Bioinformatics, Center for Informatics, City of Hope National Medical Center, Duarte, California, USA
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  • Hanjun Qin
    Affiliations
    Beckman Research Institute, City of Hope National Medical Center, Duarte, California, USA

    Department of Integrative Genomics, City of Hope National Medical Center, Duarte, California, USA
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  • Sung Hee Kil
    Affiliations
    Division of Dermatology, Department of Surgery, City of Hope National Medical Center, Duarte, California, USA

    Beckman Research Institute, City of Hope National Medical Center, Duarte, California, USA
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  • Corey Morales
    Affiliations
    Beckman Research Institute, City of Hope National Medical Center, Duarte, California, USA

    Department of Hematology & Hematopoietic Cell Transplantation, City of Hope National Medical Center, Duarte, California, USA
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  • Daniel Schmolze
    Affiliations
    Department of Pathology, City of Hope National Medical Center, Duarte, California, USA
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  • James F. Sanchez
    Affiliations
    Beckman Research Institute, City of Hope National Medical Center, Duarte, California, USA

    Department of Hematology & Hematopoietic Cell Transplantation, City of Hope National Medical Center, Duarte, California, USA
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  • Lei Tian
    Affiliations
    Beckman Research Institute, City of Hope National Medical Center, Duarte, California, USA

    Department of Hematology & Hematopoietic Cell Transplantation, City of Hope National Medical Center, Duarte, California, USA
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  • Jianhua Yu
    Affiliations
    Beckman Research Institute, City of Hope National Medical Center, Duarte, California, USA

    Department of Hematology & Hematopoietic Cell Transplantation, City of Hope National Medical Center, Duarte, California, USA
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  • Marcin Kortylewski
    Affiliations
    Beckman Research Institute, City of Hope National Medical Center, Duarte, California, USA

    Department of Immuno-Oncology, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, USA
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  • Steven T. Rosen
    Affiliations
    Beckman Research Institute, City of Hope National Medical Center, Duarte, California, USA

    Department of Hematology & Hematopoietic Cell Transplantation, City of Hope National Medical Center, Duarte, California, USA
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  • Christiane Querfeld
    Correspondence
    Correspondence: Christiane Querfeld, Division of Dermatology, Department of Surgery, Beckman Research Institute, City of Hope National Medical Center, 1500 East Duarte Road, Duarte, California 91010, USA.
    Affiliations
    Division of Dermatology, Department of Surgery, City of Hope National Medical Center, Duarte, California, USA

    Beckman Research Institute, City of Hope National Medical Center, Duarte, California, USA

    Department of Hematology & Hematopoietic Cell Transplantation, City of Hope National Medical Center, Duarte, California, USA

    Department of Pathology, City of Hope National Medical Center, Duarte, California, USA
    Search for articles by this author
Published:November 10, 2021DOI:https://doi.org/10.1016/j.jid.2021.08.447
      Cutaneous T cell lymphoma (CTCL) is characterized by a background of chronic inflammation, where malignant CTCL cells escape immune surveillance. To study how microRNAs (miRs) regulate T-cell exhaustion, we performed miR sequencing analysis, qRT-PCR, and in situ hybridization on 45 primary CTCL samples, three healthy skin samples, and CTCL cell lines, identifying miR-155-5p, miR-130b-3p, and miR-21-3p. Moreover, miR-155-5p, miR-130b-3p, and miR-21-3p positively correlated with immune checkpoint gene expression in lesional skin samples and were enriched in the IL-6/Jak/signal transducer and activator of transcription signaling pathway by gene set enrichment analysis. Further gene sequencing analysis showed decreased mRNA expression of the major negative regulators of Jak/signal transducer and activator of transcription signaling: SOCS, PIAS, and PTPN. Transfection of MyLa and HuT78 cells with anti–miR-155-5p, anti‒miR-21-3p, and anti‒miR-130b revealed a considerable increase in SOCS proteins along with a significant decrease in the levels of activated signal transducer and activator of transcription 3 and immune checkpoint surface protein expression as well as decreased cell proliferation. Downregulation of miR-155, miR-130, and miR-21 in CTCL cell lines decreased CTCL cell growth and facilitated CD8+ T-cell–mediated cytotoxic activity, with concordant production of IFN-γ and CD107a expression. Our results describe the mechanisms of miR-induced T-cell exhaustion, which provide a foundation for developing synthetic anti-miRs to therapeutically target the tumor microenvironment in CTCL.

      Abbreviations:

      CTCL (cutaneous T cell lymphoma), IC (immune checkpoint), MF (mycosis fungoides), miR (microRNA), RNA-seq (RNA sequencing), scr (scrambled control), SS (Sézary syndrome), STAT (signal transducer and activator of transcription)
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