한빛사논문
Eun-Ji Lee a, Young Soo Kim a, Ji Hye Kim a, Kyeong Wan Woo b, Young-Hoon Park c, Jung-Hye Ha c, Wei Li a, Tae In Kim a, Byeong Kwan An d, Hyun Woo Cho b, Jung Ho Han a, Jang-Gi Choi a, Hwan-Suck Chung a,e
aKorean Medicine Application Center, Korea Institute of Oriental Medicine (KIOM), 70, Cheomdan-ro, Dong-gu, Daegu 41062, Republic of Korea
bNational Development Institute of Korea Medicine, 27, Wondogwandeok-gil, Jangheung-eup, Jangheung-gun, Jeollanam-do 59319, Republic of Korea
cNew Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation (DGMIF), 80, Cheombok-ro, Dong-gu, Daegu 41061, Republic of Korea
dNational Development Institute of Korea Medicine, 94, Hwarang-ro, Gyeongsan-si, Gyeongsangbuk-do 38540, Republic of Korea
eKorean Convergence Medical Science Major, KIOM Campus, University of Science and Technology (UST), 70, Cheomdan-ro, Dong-gu, Daegu 41062, Republic of Korea
Corresponding authors : Jang-Gi Choi, Hwan-Suck Chung
Abstract
Background: The emergence of immune checkpoint inhibitors, a novel class of immunotherapy drugs, represents a major breakthrough in cancer immunotherapy, substantially improving patient survival post-treatment. Blocking programmed death-ligand 1 (PD-L1) and programmed death protein-1 (PD-1) has demonstrated promising clinical results in various human cancer types. The US FDA has recently permitted only monoclonal antibody (mAb)-based PD-L1 or PD-1 blockers. Although these antibodies exhibit high antitumor efficacy, their size- and affinity-induced side effects limit their applicability.
Purpose: As small-molecule-based PD-1/PD-L1 blockers capable of reducing the side effects of antibody therapies are needed, this study focuses on exploring natural ingredient-based small molecules that can target hPD-L1/PD-1 using herbal medicines and their components.
Methods: The antitumor potential of evening primrose (Oenothera biennis) root extract (EPRE), a globally utilized traditional herbal medicine, folk remedy, and functional food, was explored. A coculture system was established using human PD-L1-expressed murine MC38 cells (hPD-L1-MC38s) and CD8+ tumor-infiltrating T lymphocytes (CD8+ TILs) expressing humanized PD-1. The in vivo experiments utilized a colorectal cancer (CRC) C57BL/6 J mouse model bearing MC38 cells expressing humanized PD-L1 and PD-1 proteins.
Results: EPRE and its active compound oenothein B effectively hindered the molecular interaction between hPD-L1 and hPD-1. EPRE stimulated tumor-specific T lymphocytes of a hPD-L1/PD-1 CRC mice. This action resulted in the elevated infiltration of cytotoxic CD8+T lymphocytes and subsequent tumor growth reduction. Moreover, the combined therapy of oenothein B, a PD-1/PD-L1 blocker, and FOLFOX (5-fluorouracil plus oxaliplatin) cooperatively suppressed hPD-L1-MC38s growth in the ex vivo model through activated CD8+ TIL antitumor immune response. Oenothein B exhibited a high binding affinity for hPD-L1 and hPD-1. We believe that this study is the first to uncover the inhibitory effects of EPRE and its component, oenothein B, on PD-1/PD-L1 interactions.
Conclusion: This study identified a promising small-molecule candidate from natural products that blocks the hPD-L1/PD-1 signaling pathway. These findings emphasize the potential of EPRE and oenothein B as effective anticancer drugs.
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