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

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.

Abrogation of USP7 is an alternative strategy to downregulate PD-L1 and sensitize gastric cancer cells to T cells killing

“…Patients with expression of PD-L1 on either cancer cells or on TILs prefer to respond to anti-PD-1/PD-L1 therapy 17 , 18 , 19 . Meanwhile, the expression of PD-L1 can be regulated by many factors 20 , 21 . Hence, it is critical to comprehend the pathways regulating expression and stability of PD-L1.…”

Understanding Lung Carcinogenesis from a Morphostatic Perspective: Prevention and Therapeutic Potential of Phytochemicals for Targeting Cancer Stem Cells

“…It is worth mentioning that therapeutic modulating of ion channels using phytochemical compounds in lung cancer could be a future endeavor because modulating hyperpolarization to resting membrane potential can effectively restore CSCs to their quiescence [ 178 ]. Recent mounting evidence has shown that phytochemical compounds have the potential to be used as an alternative to immune checkpoint inhibitors against Programmed cell death 1 ligand 1 (PDL1) such as the cases of EGCG and berberine [ 179 , 180 ]. Future study is still necessary to demonstrate whether the utilization of phytochemical compounds can help alleviate the resistance challenge and side effects of immunotherapy.…”

The Research on the Treatment of Metastatic Skin Cutaneous Melanoma by Huanglian Jiedu Decoction Based on the Analysis of Immune Infiltration Analysis

“…Baicalin participates in the regulation of TLRs signaling pathways to exert immunomodulatory effects, thereby inhibiting the migration of cancer cells [ 36 ]. Berberine can inhibit the expression of PD-L1 in tumor cells and activate T cells to participate in tumor immune regulation [ 37 , 38 ]. It was found that CXCL12 and CCL27 played an important role in CM metastasis, and were mainly involved in SKMC metastasis through the CXCR4-CXCR7-CXCL12 axis and CCL27-CCR10 axis [ 39 , 40 ].…”