Resveratrol targets PD-L1 glycosylation and dimerization to enhance antitumor T-cell immunity

Verdura, Sara; Cuyàs, Elisabet; Cortada, Èric; Brunet, Joan; López-Bonet, Eugeni; Martín-Castillo, Begoña; Bosch-Barrera, Joaquim; Encinar, José Antonio; Menendez, Javier A.

doi:10.18632/aging.102646

Cited by 116 publications

(102 citation statements)

References 122 publications

(178 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…25,38 Several small molecules, such as 2-deoxyglucose, metformin, and resveratrol, have been shown to cause abnormal PD-L1 glycosylation and induce its ER accumulation or decrease its stability. [39][40][41] Our data that the PD-L1 3NQ glycosylation mutant failed to induce PD-1 degradation in the coculture supported the essentiality of glycosylation for the function of PD-L1 (Figure 4(b)). However, the blockade of PD-L1 ER exporting by BMS1166 was not a consequence of inhibition of PD-L1 glycosylation, because a complete loss of N-glycosylation induced by TM did not affect the ER exporting and membrane localization of PD-L1 ( Figure S5).…”

Section: Discussionsupporting

confidence: 62%

Small-molecule PD-L1 inhibitor BMS1166 abrogates the function of PD-L1 by blocking its ER export

Chen

et al. 2020

OncoImmunology

View full text Add to dashboard Cite

Therapeutic monoclonal antibodies against the PD-L1/PD-1 (programmed death ligand-1/programmed cell death protein-1) axis have achieved great successes in cancer treatments, but the development of smallmolecule immunomodulators of the pathway has lagged far behind. We established a cellular coculture assay with two stable transfectant cell lines, a PD-L1-expressing tumor cell line PC9/PD-L1 and a PD-1-expressing T cell line Jurkat/PD-1. Western blotting analyses were used to monitor the PD-L1/PD-1 interaction and signaling. We analyzed PD-L1 glycosylation by lectin binding assay and glycosidase digestion, and examined subcellular localization of PD-L1 by immunocytochemical staining. Luciferase assay and real-time PCR were used to evaluate T cell activation in the coculture experiments. We found that coculturing of the PC9/PD-L1 cells with the Jurkat/PD-1 cells induced a lysosomal degradation of PD-1. A smallmolecule PD-L1 inhibitor BMS1166 developed by Bristol-Myers Squibb inhibited the coculture-induced PD-1 degradation through a unique mechanism. BMS1166 specifically affected PD-L1 glycosylation and prevented transporting of the under-glycosylated form of PD-L1 from endoplasmic reticulum (ER) to Golgi, leading to accumulation of PD-L1 in ER. In doing so, BMS1166 blocked PD-L1/PD-1 signaling. Coculturing PD-L1-expressing cells with PD-1-expressing cells induced degradation of PD-1, which could be used as a readout to identify inhibitors of PD-L1/PD-1 signaling. The small-molecule PD-L1 inhibitor BMS1166 abolished the glycosylation and maturation of PD-L1 by blocking its exporting from ER to Golgi. Our study discovered a new strategy to identify inhibitors of the PD-L1/PD-1 signaling pathway and to develop new drugs for the treatment of cancer.

show abstract

Section: Discussionsupporting

confidence: 62%

Small-molecule PD-L1 inhibitor BMS1166 abrogates the function of PD-L1 by blocking its ER export

Chen

et al. 2020

OncoImmunology

View full text Add to dashboard Cite

show abstract

“…When cancer cells were previously exposed to resveratrol, cytotoxic T-lymphocyte activity was notably exacerbated. These results suggest that resveratrol exerts anti-cancer property by restoring T-cell function [59].…”

Section: Synergistic Effects Of Combined Polyphenols Administrationmentioning

confidence: 78%

Natural Polyphenols Targeting Senescence: A Novel Prevention and Therapy Strategy for Cancer

Bian

Wei

Zhao

et al. 2020

IJMS

View full text Add to dashboard Cite

Cancer is one of the most serious diseases endangering human health. In view of the side effects caused by chemotherapy and radiotherapy, it is necessary to develop low-toxic anti-cancer compounds. Polyphenols are natural compounds with anti-cancer properties and their application is a considerable choice. Pro-senescence therapy is a recently proposed anti-cancer strategy and has been shown to effectively inhibit cancer. It is of great significance to clarify the mechanisms of polyphenols on tumor suppression by inducing senescence. In this review, we delineated the characteristics of senescent cells, and summarized the mechanisms of polyphenols targeting tumor microenvironment and inducing cancer cell senescence for cancer prevention and therapy. Although many studies have shown that polyphenols effectively inhibit cancer by targeting senescence, it warrants further investigation in preclinical and clinical studies.

show abstract

“…Another mechanism underlying the antitumor effects of resveratrol could be its regulation of PD-L1 expression in the tumor since previous studies have demonstrated that it reduces PDL1 expression in cancer cells and interferes with PDL1 dimerization and glycosylation. 44 , 45 Thus, resveratrol has a broad impact on antitumor immunity.…”

Section: Discussionmentioning

confidence: 99%

Resveratrol exerts antitumor effects by downregulating CD8 ⁺ CD122 ⁺ Tregs in murine hepatocellular carcinoma

et al. 2020

View full text Add to dashboard Cite

CD4 + Foxp3 + regulatory T cells (Tregs) in the tumor microenvironment restrain antitumor immunity, resulting in tumor aggression and poor survival in hepatocellular carcinoma (HCC). CD8 + CD122 + Tregs have been previously shown to be more potent in immunosuppression than are CD4 + Foxp3 + Tregs. Previous studies have demonstrated that resveratrol exerts its anti-cancer effects by downregulating CD4 + Foxp3 + and M2-like macrophages, two key immunoregulatory cells that maintain the immunosuppressive tumor microenvironment. In this study, we found that resveratrol inhibited the tumor growth in a subcutaneous Hepa1-6 HCC model and decreased the frequency of CD8 + CD122 + Tregs in the tumor as well as lymph nodes and spleen of the tumor-bearing mice. It also increased the percentage of IFN-γ-expressing CD8 + T cells in the tumor and peripheral lymphoid organs. The antitumor effects of resveratrol were partially reversed by the adoptive transfer of exogenous CD8 + CD122 + Tregs into the tumor-bearing mice. Meanwhile, resveratrol treatment downregulated immunosuppressive cytokines, including TGF-β1 and interleukin-10, in the tumor while elevating antitumor cytokines, TNF-α and IFN-γ. It also inhibited the activation of STAT3 signaling in the tumor. As expected, resveratrol reduced the percentage of M2-like macrophages in the mice. Importantly, resveratrol suppressed orthotopic H22 tumor growth and decreased the frequency of CD8 + CD122 + Tregs and M2-like macrophages in the tumor-bearing mice. Furthermore, our studies showed that resveratrol, at non-cytotoxic concentrations, inhibited CD8 + CD122 + Treg differentiation from CD8 + CD122 − T cells in vitro . Thus, our studies unveiled a new immune mechanism underlying the immunosuppressive tumor microenvironment and demonstrated that resveratrol could help reverse it by diminishing CD8 + CD122 + Tregs.

show abstract

Resveratrol targets PD-L1 glycosylation and dimerization to enhance antitumor T-cell immunity

Cited by 116 publications

References 122 publications

Small-molecule PD-L1 inhibitor BMS1166 abrogates the function of PD-L1 by blocking its ER export

Small-molecule PD-L1 inhibitor BMS1166 abrogates the function of PD-L1 by blocking its ER export

Natural Polyphenols Targeting Senescence: A Novel Prevention and Therapy Strategy for Cancer

Resveratrol exerts antitumor effects by downregulating CD8 ⁺ CD122 ⁺ Tregs in murine hepatocellular carcinoma

Contact Info

Product

Resources

About

Resveratrol targets PD-L1 glycosylation and dimerization to enhance antitumor T-cell immunity

Cited by 116 publications

References 122 publications

Small-molecule PD-L1 inhibitor BMS1166 abrogates the function of PD-L1 by blocking its ER export

Small-molecule PD-L1 inhibitor BMS1166 abrogates the function of PD-L1 by blocking its ER export

Natural Polyphenols Targeting Senescence: A Novel Prevention and Therapy Strategy for Cancer

Resveratrol exerts antitumor effects by downregulating CD8 + CD122 + Tregs in murine hepatocellular carcinoma

Contact Info

Product

Resources

About

Resveratrol exerts antitumor effects by downregulating CD8 ⁺ CD122 ⁺ Tregs in murine hepatocellular carcinoma