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Inhibition of UBE2N in regulatory T-cells boosts immunity against cancer

Wanying Miao, Vaibhav Jain, Madison Han

    Biorxiv : the Preprint Server for Biology
    |November 1, 2024
    PubMed

    Insights

    Targeting UBE2N in regulatory T (Treg) cells converts them into anti-cancer effectors. This strategy enhances cytotoxic T-cell responses and prolongs survival without causing autoimmunity, offering a novel cancer immunotherapy approach.

    Area of Science:

    • Immunology
    • Oncology
    • Molecular Biology

    Background:

    • Regulatory T (Treg) cells suppress immune responses, aiding cancer immune evasion but posing challenges for cancer therapies due to potential autoimmunity.
    • Depleting Tregs is a therapeutic strategy, yet its clinical application is limited by the risk of autoimmune reactions.

    Purpose of the Study:

    • To investigate the role of UBE2N in Treg function and its potential as a therapeutic target for cancer immunotherapy.
    • To explore the mechanism by which UBE2N deletion impacts Treg immunosuppressive functions and anti-tumor immunity.

    Main Methods:

    • Temporal deletion of Ube2n in Tregs (Ube2n Treg-KO) in adult mice.
    • Assessment of anti-tumor effects and survival benefits in cancer models.
    • Single-cell transcriptomic analysis to identify molecular changes in UBE2N-deleted Tregs.
    • Investigation of UBE2N's role in c-Myc protein stability and degradation pathways.

    Main Results:

    • Ube2n deletion in Tregs led to their expansion and activation, promoting cytotoxic CD8+ T-cell responses against cancer.
    • Ube2n-deleted Tregs shifted from an immunosuppressive to an effector-like phenotype, characterized by c-Myc target gene downregulation.
    • UBE2N was found to stabilize c-Myc protein by inhibiting its proteasomal degradation via K48-ubiquitination.
    • Adoptive transfer of T-cells demonstrated the anti-tumor efficacy, and UBE2N/c-Myc axis was identified as a potential therapeutic target.

    Conclusions:

    • Targeting UBE2N in Tregs can reprogram them into anti-tumor effector cells, enhancing anti-cancer immunity without inducing autoimmunity.
    • The UBE2N/c-Myc signaling pathway represents a novel and druggable target for overcoming Treg-mediated immune suppression in cancer.

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