FBXO38 mediates PD-1 ubiquitination and regulates anti-tumour immunity of T cells
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450 citations
Cites background from "FBXO38 mediates PD-1 ubiquitination..."
...Furthermore, IL-2, the major growth factor of T cells, can rescue FBXO38 level in tumor-infiltrating T cells via STAT5-mediated transcriptional regulation.(22) Notably, FBXO38 expression levels in tumor infiltrating lymphocytes (TILs) are even lower than in naïve T cells....
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...This likely represents one of the several working mechanisms of IL2 in treating cancer.(22) A rationally-designed peptide PD-LYSO, containing a PD-L1-binding sequence and a lysosomal-sorting signal sequence from HIP1R, can target PD-L1 for lysosomal degradation....
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...TCR signaling without concomitant CD28 signaling was found to be the cause of FBXO38 downregulation.(22) Persistent exposure to tumor antigen and low CD80/86 expression on tumor cells(25) therefore could explain the reduced FBXO38 expression in TILs....
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257 citations
Cites background from "FBXO38 mediates PD-1 ubiquitination..."
...FBXO38, an E3 ligase of PD-1, mediates K48-linked polyubiquitination and subsequent proteasome degradation in activated T cells.(501) Additionally, COP9 signalosome 5 (CSN5) is required for PD-L1 stabilization by inhibiting its ubiquitination and degradation in cancer cells....
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225 citations
Cites background from "FBXO38 mediates PD-1 ubiquitination..."
...X. Meng, X. Liu, X. Guo, S. Jiang, T. Chen, Z. Hu, H. Liu, Y. Bai, M. Xue, R. Hu, S.-c. Sun, X. Liu, P. Zhou, X. Huang, L. Wei, W. Yang, C. Xu, FBXO38 mediates PD-1 ubiquitination and regulates anti-tumour immunity of T cells....
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...PD-1 expression may also be regulated by E3 ligase FBXO38, which mediates K48-linked polyubiquitination at the PD-1 K233 site and subsequent proteasome degradation (Fig....
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...Treatment/targets Mechanism of action Outcome in T cells Inhibition of PD-1 core fucosylation (17) Decreased surface expression of PD-1 on T cells Increased T cell function Enhancing expression of ubiquitin ligase FBXO38 (18) Increased PD-1 degradation in T cells Increased T cell function EGFR inhibitors + PD-1 blockade (19) Decreased PD-L1 expression Increased T cell function CSN5 inhibitors (or curcumin) + CTLA-4 blockade (20) Decreased PD-L1 expression Increased T cell function CMTM4/6 degradation (26, 27) Decreased PD-L1 expression Increased T cell function Antibodies against glycosylated PD-L1 (21) PD-L1 internalization and degradation Increased T cell function Patsoukis et al., Sci. Adv....
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...Enhancing expression of ubiquitin ligase FBXO38 (18) Increased PD-1 degradation in T cells Increased T cell function...
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References
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