Green Tea Catechin Is an Alternative Immune Checkpoint Inhibitor that Inhibits PD-L1 Expression and Lung Tumor Growth.

Anchalee Rawangkan,Yoshihiko Shimizu,Yasuhito Kobayashi,Hirota Fujiki,Pattama Wongsirisin,Masami Suganuma,Keisuke Iida,Kozue Namiki

doi:10.3390/molecules23082071

Abstract

The anticancer activity of immune checkpoint inhibitors is attracting attention in various clinical sites. Since green tea catechin has cancer-preventive activity in humans, whether green tea catechin supports the role of immune checkpoint inhibitors was studied. We here report that (−)-epigallocatechin gallate (EGCG) inhibited programmed cell death ligand 1 (PD-L1) expression in non–small-cell lung cancer cells, induced by both interferon (IFN)-γ and epidermal growth factor (EGF). The mRNA and protein levels of IFN-γ–induced PD-L1 were reduced 40–80% after pretreatment with EGCG and green tea extract (GTE) in A549 cells, via inhibition of JAK2/STAT1 signaling. Similarly, EGF-induced PD-L1 expression was reduced about 37–50% in EGCG-pretreated Lu99 cells through inhibition of EGF receptor/Akt signaling. Furthermore, 0.3% GTE in drinking water reduced the average number of tumors per mouse from 4.1 ± 0.5 to 2.6 ± 0.4 and the percentage of PD-L1 positive cells from 9.6% to 2.9%, a decrease of 70%, in lung tumors of A/J mice given a single intraperitoneal injection of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). In co-culture experiments using F10-OVA melanoma cells and tumor-specific CD3+ T cells, EGCG reduced PD-L1 mRNA expression about 30% in F10-OVA cells and restored interleukin-2 mRNA expression in tumor-specific CD3+ T cells. The results show that green tea catechin is an immune checkpoint inhibitor.

Highlights

Blockade of programmed cell death ligand 1 (PD-L1)/programmed cell death 1 (PD-1) immune checkpoints by monoclonal antibodies has shown measurable success in cancer therapy against a variety of tumor types, including non–small-cell lung cancer (NSCLC) [1,2]
We studied the relationship between inhibition of PD-L1 expression and lung tumor growth by giving water containing 0.3% green tea extract (GTE), a freeze-dried form of green tea infusion, to A/J mice treated with a tobacco-specific carcinogen, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), in vivo
We found that epigallocatechin gallate (EGCG) and GTE inhibited both IFN-γ– and epidermal growth factor (EGF)-induced PD-L1 expression by inhibiting two signaling pathways, JAK2/STAT1 and EGF receptor (EGFR)/Akt, in human NSCLC

Summary

Introduction

Blockade of programmed cell death ligand 1 (PD-L1)/programmed cell death 1 (PD-1) immune checkpoints by monoclonal antibodies has shown measurable success in cancer therapy against a variety of tumor types, including non–small-cell lung cancer (NSCLC) [1,2]. Binding of PD-L1 to PD-1 inhibits T cell effector function by inducing exhaustion and apoptosis of T cells, resulting in an immunosuppressive state [3]. Molecules 2018, 23, 2071 immune escape and cancer progression. Immunotherapy targeting PD-L1/PD-1 signaling is being used for treatment of advanced lung cancers, the benefit is limited to the early stages, because antibody-based checkpoint inhibitors are associated with unique immune-related adverse effects and high costs [4]. A phytochemical, inhibits interferon (IFN)-γ–induced PD-L1 protein [6].

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Conclusion