论文题目：Berberine diminishes cancer cell PD-L1 expression and facilitates antitumor immunity via inhibiting the deubiquitination activity of CSN5

作者：Yang Liu, Xiaojia Liu;, Na Zhang;, Mingxiao Yin, Jingwen Dong, Qingxuan Zeng, Genxiang Mao, Danqing Song, Lu Liu, Hongbin Deng

期刊名称：Acta Pharm Sin B

IF：7.097

年份：2020

卷期页：10（12）:2299-2312

Programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) blocking therapy has become a major pillar of cancer immunotherapy. Compared with antibodies targeting, small-molecule checkpoint inhibitors which have favorable pharmacokinetics are urgently needed. Here we identified berberine (BBR), a proven anti-inflammation drug, as a negative regulator of PD-L1 from a set of traditional Chinese medicine (TCM) chemical monomers. BBR enhanced the sensitivity of tumour cells to co-cultured T-cells by decreasing the level of PD-L1 in cancer cells. In addition, BBR exerted its antitumor effect in Lewis tumor xenograft mice through enhancing tumor-infiltrating T-cell immunity and attenuating the activation of immunosuppressive myeloid-derived suppressor cells (MDSCs) and regulatory T-cells (Tregs). BBR triggered PD-L1 degradation through ubiquitin (Ub)/proteasome-dependent pathway. Remarkably, BBR selectively bound to the glutamic acid 76 of constitutive photomorphogenic-9 signalosome 5 (CSN5) and inhibited PD-1/PD-L1 axis through its deubiquitination activity, resulting in ubiquitination and degradation of PD-L1. Our data reveals a previously unrecognized antitumor mechanism of BBR, suggesting BBR is small-molecule immune checkpoint inhibitor for cancer treatment.Keywords: AMC, 7-amino-4-methylcoumarin; BBR, berberine; Baf, bafilomycin; Berberine; CHX, cycloheximide; COP9 signalosome 5; CQ, chloroquine; CSN5, COP9 signalosome 5; IB, immunoblotting; ICB, immune checkpoint blockade; IFN-γ, interferon-gamma; IHC, immunohistochemistry; Immune checkpoint blockade; MDSCs, myeloid-derived suppressor cells; NFAT, nuclear factor of activated T-cells; NSCLC, non-small cell lung cancer; PD-1, programmed cell death-1; PD-1/PD-L1 axis; PD-L1; PD-L1, programmed cell death ligand-1; SPR, surface plasmon resonance; T-cell immunity; TCM, traditional Chinese medicine; TILs, tumor-infiltrating lymphocytes; TNF-α, tumor necrosis factor-α; Tregs, regulatory T-lymphocytes; Ub, ubiquitin; qRT-PCR, quantitative real-time polymerase chain reaction.