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.
Highlights
Immune checkpoint inhibitors are being increasingly used in the treatment of malignant tumors, and they are revolutionizing treatment approaches and increasing survival expectations in cancer patients [1, 2]
We investigated the ability of the methylene chloride (MC), ethyl acetate (EA), and n-butanol (BuOH) fractions of Salvia plebeia R. Br. extract (SPE) to inhibit the PD-1/PD-L1 interaction
CD8+ T-cell infiltration in the SPE group was significantly higher than vehicle group treatment (Figure 7). These results suggest that SPE showed ant-tumor activity in hPD-L1 knock-in MC38 tumor-bearing humanized PD-1 mouse model
Summary
Immune checkpoint inhibitors are being increasingly used in the treatment of malignant tumors, and they are revolutionizing treatment approaches and increasing survival expectations in cancer patients [1, 2]. Antibody therapies have sometimes been reported to cause serious grade 3 and 4 adverse events; up to 55% of ipilimumab-treated patients, up to 43% of nivolumabtreated patients, 11–14% of pembrolizumab-treated patients, and 54–86% of ipilimumab plus nivolumab-treated patients [9]. These issues have increased interest in the development of alternative small molecule interventions that include peptidomimetics and peptides targeting the PD-1/PD-L1 immune checkpoint pathway and interfere with the broad clinical application of antibodies [10, 11]. Small molecules for targeting the PD-1/PD-L1 immune checkpoint pathway are under development, but no molecule has yet been approved [11]
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