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

• DOI: 10.1016/j.apsb.2020.06.014
• Publication Date: 2020-06-30T19:21:11Z
• Authors: Yang Liu; Xiaojia Liu; Na Zhang; Mingxiao Yin; Jingwen Dong; Qingxuan Zeng; Genxiang Mao; Danqing Song; Lu Liu; Hongbin Deng
• Keywords: PD-L1; 0301 basic medicine; T-cell immunity; 03 medical and health sciences; Berberine; COP9 signalosome 5; Original Article; Therapeutics. Pharmacology; RM1-950; Immune checkpoint blockade; PD-1/PD-L1 axis; 3. Good health

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.