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

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

doi:10.1016/j.apsb.2020.06.014

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

Acta Pharm Sin B. 2020 Dec;10(12):2299-2312. doi: 10.1016/j.apsb.2020.06.014. Epub 2020 Jun 30.

Authors

Yang Liu¹, Xiaojia Liu¹, Na Zhang¹, Mingxiao Yin¹, Jingwen Dong¹, Qingxuan Zeng¹, Genxiang Mao², Danqing Song¹, Lu Liu³, Hongbin Deng^{1

4}

Affiliations

¹ Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China.
² Zhejiang Provincial Key Lab of Geriatrics, Department of Geriatrics, Zhejiang Hospital, Hangzhou 310013, China.
³ Qingdao Women and Children's Hospital, Qingdao University, Qingdao 266034, China.
⁴ State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.

Abstract

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.