Disrupting USP14-mediated PARP1 dynamics reinstates MIC-A/B-driven antigen-independent CD8+ T cell killing in glioma - PubMed
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- #immunotherapy
- #USP14
- #glioma
- Antigen loss is a major resistance mechanism to immunotherapy in glioma.
- MIC-A/B, stress-inducible ligands, activate NKG2D on immune cells but their reduced expression in glioma is unclear.
- USP14 identified as a key regulator of MIC-A/B via deubiquitinase screening in mouse glioma models.
- USP14 stabilizes PARP1 through K63-linked deubiquitination, reducing NFIL3 binding to the MIC-A/B promoter.
- Inhibition of USP14 activates CD8+ T cells in a MIC-A/B-NKG2D-dependent, antigen-independent manner.
- Combining USP14 inhibition with PD1 blockade enhances antitumor immunity and prolongs survival in glioma.
- Clinical data links USP14 overexpression with PARP1 levels and dysfunctional CD8+ T cell infiltration in glioma.