The authors examined the cellular response to DHODH inhibition and found that treatment with the DHODH inhibitor brequinar (BQ) or the clinically approved DHODH inhibitor teriflunomide led to a dose- and duration-dependent upregulation of genes involved in the antigen presentation pathway (APP) and increased cell surface expression of MHC-I across diverse cancer cell lines.
This effect was strictly dependent on pyrimidine nucleotide depletion, as it was abrogated by supplementation with the pyrimidine nucleoside uridine. Mechanistic studies revealed that the APP induction was independent of canonical regulators like IFN-JAK-STAT, NF-κB, and cGAS-STING-TBK1 pathways, but required the activity of the positive transcription elongation factor B (P-TEFb), which controls RNA polymerase II elongation.
In a syngeneic mouse melanoma model, BQ monotherapy showed impressive single-agent efficacy and significantly prolonged survival when combined with dual immune checkpoint blockade (anti-CTLA-4 and anti-PD-1) in a sequential treatment regimen, but not when administered concurrently. These results demonstrate that DHODH inhibition can enhance cancer immunotherapy by increasing tumor antigen presentation and provide a rationale for combining DHODH inhibitors with immune checkpoint blockade.
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by Mullen,N. J.... lúc www.biorxiv.org 04-05-2023
https://www.biorxiv.org/content/10.1101/2023.04.03.535399v2Yêu cầu sâu hơn