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Abstract Tumor-infiltrated regulatory T-cells (Treg) restrict the function of effector T-cells and thereby promote tumor growth. Disrupting the immunosuppression of Treg cells presents an attractive strategy for cancer immunotherapy; However, the risk of autoimmunity, resulting from systemic Treg depletion, limits its therapeutic effectiveness. Here, we show that genetic depletion of Ube2n in Treg cells inhibits tumor growth which is correlated with a markedly enhanced infiltration of cytotoxic immune cells. Notably, the deletion of Ube2n in a fraction of Treg cells was sufficient to produce a long-lasting anti-tumor effect, without apparent systemic autoimmune responses. The antitumor effect persists following adoptive T-cell transfer to an otherwise immunodeficient mouse tumor model. Through flow cytometry, immunostaining and T-cell targeted single-cell sequencing analyses, we demonstrate that the loss of Ube2n dampens Treg suppressive function, as indicated by markedly increased numbers of cytotoxic CD8 T-cells in the tumor microenvironment (TME). Further, differentially expressed genes analyses show a downregulation of Mki67 and an upregulation of Ifng in Ube2n deficient Tregs, concomitant with amplification and activation of effector T-cells. Our findings uncover a hitherto unexplored role of Ube2n in orchestrating the differentiation and functions of Treg in TME, highlighting the therapeutic potential of targeting this pathway to enhance and reprogram anti-tumor immunity. Citation Format: Wanying Miao, Yingai J. Jin, Vaibhav Jain, Simon Gregory, Jennifer Y. Zhang. Targeting regulatory T cells to boost immunity against melanoma abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 2919.
Miao et al. (Fri,) studied this question.