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bioRxiv · 10.1101/2024.10.22.619436

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

Miao, W.·Jain, V.·Han, M.·Jin, Y. J.·Beasley, G. M.·Starczynowski, D. T.·Gregory, S. G.·Zhang, J. Y.
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Abstract

Regulatory T (Treg) cells prevent autoimmunity and facilitate cancer immune evasion. Depletion of Tregs is a promising cancer therapy, but risks of autoimmune reactions hamper its clinical translation. Here, we demonstrate that temporally induced deletion of Ube2n in Tregs (Ube2nTreg-KO) of adult mice results in a robust expansion and activation of cytotoxic CD8+ T-cells in response to cancer cell challenges, producing a long-lasting survival benefit without autoimmune complications. The anti-tumor effect persists following adoptive T-cell transfer to T-cell-deficient Rag1-knockout mice. Single-cell transcriptomic analysis revealed that UBE2N deletion shifted immunosuppressive Tregs to effector-like T-cells. This shift is characterized by the downregulation of c-Myc target genes, resembling that observed in tumor-infiltrating Tregs of melanoma patients. Further analyses confirm that UBE2N maintains c-Myc protein stability via suppression of K48-Ubiquitin-mediated proteasomal degradation. Taken together, our studies uncover a hitherto unexplored and potentially druggable UBE2N/c-Myc signaling axis to eradicate Treg-enabled cancer immune escape.

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Miao, W., Jain, V., Han, M., Jin, Y. J., Beasley, G. M., Starczynowski, D. T., Gregory, S. G., Zhang, J. Y.. 2024-10-25. Inhibition of UBE2N in regulatory T-cells boosts immunity against cancer. https://doi.org/10.1101/2024.10.22.619436

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