Unripe Black Raspberry (Rubus coreanus Miquel) Extract and Its Constitute, Ellagic Acid Induces T Cell Activation and Antitumor Immunity by Blocking PD-1/PD-L1 Interaction

Abstract

Rubus coreanus Miquel (R. coreanus) is a unripen fruit of black raspberry native to eastern Asia. It is used as traditional oriental medicine and supplementary foods for centuries. Previous studies have shown that the R. coreanus extract (RCE) and its main constitute ellagic acid possess diverse biological activities. However, the effects of RCE on antitumor immunity and T cell function were not fully understood. The present study describes the anti-tumor effect of RCE in humanized PD-1 mice by blocking PD-1/PD-L1 interaction. Competitive enzyme-linked immunosorbent assay (ELISA) and pull down assay were performed to elucidate the binding properties of RCE in vitro. Cellular PD-1/PD-L1 blockade activities were measured by T cell receptor (TCR)-induced nuclear factor of activated T cells-luciferase activity in co-cultured cell models with PD-1/NFAT Jurkat and PD-L1/aAPC CHO-K1 cells. The in vivo efficacy of RCE was confirmed in humanized PD-1 mice bearing MC38 colorectal tumor. RCE and ellagic acid dose-dependently block the binding of PD-1 to PD-L1. Moreover, oral administration of RCE showed the potent anti-tumor activity similar to anti-PD-1 antibody. The present study suggests that RCE possesses potent anti-tumor effect via PD-1/PD-L1 blockade, and ellagic acid is the main compound in RCE. Thus, we provide new aspects of RCE as an immunotherapeutic agent.

Sanguisorbae Radix Suppresses Colorectal Tumor Growth Through PD-1/PD-L1 Blockade and Synergistic Effect With Pembrolizumab in a Humanized PD-L1-Expressing Colorectal Cancer Mouse Model

“…Moreover, the MC38 used in vivo in this study is derived from tumors induced by carcinogen and established in C57BL/6 mice and represents a microsatellite-unstable CRC cell line ( 31 ). We have previously reported the PD-1/PD-L1-inhibiting abilities of medicinal herbs including Salvia plebeia alone and Rubus coreanus alone in vivo ( 20 , 32 ). Here, we found that SRE in combination with anti-PD-1 antibodies in vivo is a potent PD-1/PD-L1 inhibitor.…”

Small molecule inhibitors against PD-1/PD-L1 immune checkpoints and current methodologies for their development: a review

“…Kim et al reported that a black raspberry ( Rubus coreanus Miquel) extract (RCE) interrupted the binding of PD-1 and PD-L1 with an IC 50 value of 83.8 ± 4.7 μg/mL in the competitive ELISA assay [ 118 ]. PD-L1 aAPC/CHO-K1 cell co-culture based assay revealed that RCE increased the production of IL-2 by 1.8-fold with an EC 50 value of 56.15 ± 14.35 μg/mL, as compared to the control group.…”

“…Ellagic acid was shown to block PD-1/PD-L1 interaction in a concentration-dependent manner with an IC 50 value of 22.92 μg/mL (Table 1 ). In addition, ellagic acid-conjugated sepharose 4B beads pull-down assay showed that ellagic acid was able to directly bind PD-1 and PD-L1 and interrupt their binding capacity [ 118 ].…”

SR-5, the specific ratio of Korean multi-herbal formula: An evaluation of antiulcerogenic effects on experimentally induced gastric ulcers in mice

“…Based on ethnopharmacological information, our previous hepatoprotective experiments, 15 and the reported antioxidant and anti-inflammatory effects and safety data, we selected 12 Korean medicinal herbs: soybean sprouts, 16,17 Oenanthe javanica (Blume) DC., 18 immature Citrus reticulata Blanco peel, 19 Hovenia dulcis Thunb., 20,21 immature Rubus coreanus Miq., 22,23 Artemisia capillaris Thunb., 24 Chaenomeles sinensis (Dum. Cours.)…”

“…Potent anti-ulcer agents used in traditional Korean medicine approaches that have strong antioxidant effects, such as Artemisia asiatica extract (Stillen Ô , Dong-A Pharmaceuticals, Korea), are also commercially available. 14 Based on ethnopharmacological information, our previous hepatoprotective experiments, 15 and the reported antioxidant and anti-inflammatory effects and safety data, we selected 12 Korean medicinal herbs: soybean sprouts, 16,17 Oenanthe javanica (Blume) DC., 18 immature Citrus reticulata Blanco peel, 19 Hovenia dulcis Thunb., 20,21 immature Rubus coreanus Miq., 22,23 Artemisia capillaris Thunb., 24 Chaenomeles sinensis (Dum. Cours.)…”