Anticancer Effect of Salvia plebeia and Its Active Compound by Improving T-Cell Activity via Blockade of PD-1/PD-L1 Interaction in Humanized PD-1 Mouse Model

Abstract

Immune checkpoint inhibitors, increasingly used to treat malignant tumors, are revolutionizing cancer treatment by improving the patient survival expectations. Despite the high antitumor efficacy of antibody therapeutics that bind to PD-1/PD-L1, study on small molecule-based PD-1/PD-L1 inhibitors is required to overcome the side effects of antibody therapeutics caused by their size and affinity. Herein, we investigated antitumor potential of Salvia plebeia R. Br. extract (SPE), which has been used as a traditional oriental medicine and food in many countries, and its components by the blockade of PD-1/PD-L1 interaction. SPE and its component cosmosiin effectively blocked the molecular interaction between PD-1 and PD-L1. SPE also inhibited tumor growth by increasing CD8+ T-cells in the tumor through the activation of tumor-specific T-cells in a humanized PD-1 mouse model bearing hPD-L1 knock-in MC38 colon adenocarcinoma tumor. This finding presents a preclinical strategy to develop small molecule-based anticancer drugs targeting the PD-1/PD-L1 immune checkpoint pathway.

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

“…We hypothesized that SRE induces antitumor responses to blockade PD-1/PD-L1, as T cell activation by medicinal herb extracts has previously been reported ( 20 ). To confirm the cytotoxicity of SRE against murine CRC hPD-L1 MC38 cells and hPD-L1 MC38 cell-bearing hPD-1 mice-isolated splenocytes, cells were incubated with various concentrations of SRE for 72 hours.…”

“…To elucidate the effect of SRE on TCR activation, we conducted coculture systems using human PD-1-expressing Jurkat T cells that expressed NFAT-derived luciferase reporter (hPD-1/NFAT Jurkat cells) and human PD-L1-expressing aAPC/CHO-K1 cells designed to activate cognate TCR (hPD-L1/TCR CHO-K1 cells). The cell culture model was established to evaluate the effect of PD-1/PD-L1 blockade ( 20 ). To examine the cytotoxic effects of SRE, hPD-1 effector cells and hPD-L1/TCR CHO-K1 cells were treated with the indicated concentration (0–50 μg/mL) of SRE for 24 hours.…”

“…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

“…Choi et al reported that Salvia plebeia R. Br. extract (SPE) blocked the interactions between PD-1 and PD-L1 [ 115 ]. Two flavonoids including apigenin and cosmosiin (Fig.…”

Augmented Antitumor Effect of Unripe Rubus coreanus Miquel Combined with Oxaliplatin in a Humanized PD-1/PD-L1 Knock-In Colorectal Cancer Mouse Model

“…Recently, using competitive ELISA, we showed Rhus vernicifua Stokes alone as an active inhibitor with a PD-1/PD-L1 blocking effect [ 31 ]. In addition, we previously reported the anticancer properties of several herbal medications: Sanguisorbae radix, Salvia plebeia , and RCE were each used alone as monotherapy via the inhibition of PD-1/PD-L1, and these were verified to be effective at non-toxic concentrations [ 28 , 32 , 33 ]. To confirm the clinical applicability of these herbal medications and expand their use, we sought to develop an innovative combination therapy with RCE aimed at blocking PD-1/PD-L1 binding.…”