The E3 Ligase FBXO38 Controls PD-1 Expression and Antitumor Immunity

Aberrant upregulation of the immune checkpoint protein PD-1 on intratumoral T cells results in impaired antitumor immunity, emphasizing the importance of understanding the mechanisms that control PD-1 expression. Transcriptional regulation of the gene encoding PD-1 has been well characterized, but whether PD-1 protein levels are also regulated has not been determined. Meng, Liu, and colleagues found that PD-1 protein was ubiquitinated following internalization from the cell surface and was subsequently degraded by the proteasome in activated human T cells. The F-box protein FBXO38, a member of the SKP1–CUL1–F-box protein family of E3 ubiquitin ligases, interacted with PD-1 and decreased PD-1 cell-surface expression on activated T cells. Consistent with a role in mediating PD-1 downregulation, FBXO38 directly induced Lys48-linked polyubiquitination of internalized PD-1 at Lys233, leading to PD-1 proteasomal degradation. Mice with conditional deletion of Fbxo38 in T cells did not exhibit changes in T-cell receptor or CD28 signaling, but displayed higher cell-surface levels of PD-1 on tumor-infiltrating T cells and enhanced tumor progression compared to wild-type mice. This increase in tumor growth was reversed by anti–PD-1 therapy, implicating PD-1 as the main target of FBXO38. FBXO38 transcription was downregulated in both human and mouse tumor-infiltrating CD8⁺PD-1⁺ T cells, but could be restored by treatment with IL2, which stimulated FBXO38 transcription via the downstream transcription factor STAT5. Moreover, IL2 administration decreased PD-1 expression on the surface of tumor-infiltrating T cells and showed better antitumor effects in wild-type mice than mice with T cell–specific deletion of Fbxo38. These results define FBXO38 as a critical mediator of PD-1 protein degradation that is required for maintenance of antitumor immunity and suggest targeting IL2-mediated regulation of FBXO38 expression as a potential strategy to block PD-1 signaling in tumors.

Meng X, Liu X, Guo X, Jiang S, Chen T, Hu Z, et al. FBXO38 mediates PD-1 ubiquitination and regulates anti-tumour immunity of T cells. Nature 2018;564:130–5.

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