Ryu Ji Hyeon, Song Min Seok, Nyiramana Marie Merci, Prayoga Anjas Happy, Cao Dang Long, Lee Gyeong-Won, Kwon Hyuk-Kwon, Kang Dawon
Research Institute for Convergence of Biomedical Science and Technology Pusan National University Yangsan Hospital Yangsan Republic of Korea.
Department of Physiology, College of Medicine Gyeongsang National University Jinju Republic of Korea.
Food Sci Nutr. 2024 Dec 2;13(1):e4644. doi: 10.1002/fsn3.4644. eCollection 2025 Jan.
Our previous study highlighted the anticancer potential of sea hare hydrolysate (SHH), particularly its role in regulating macrophage polarization and inducing pyroptotic death in lung cancer cells through the inhibition of signal transducer and activator of transcription 3 (STAT3). These findings prompted us to investigate additional features of immune-oncology (I-O) agents or adjuvants, such as programmed cell death protein 1 (PD-1)/programmed death ligand 1 (PD-L1) inhibition and their association with rheumatoid arthritis (RA) risk, to explore the potential of SHH as an I-O agent or adjuvant. In this study, we investigated the effects of SHH on PD-L1 levels in various cancer cell types and assessed its effectiveness in treating RA, a common side effect of I-O agents. Our results showed a marked reduction in PD-L1 levels in multiple cancer cell lines and decreased PD-1 and PD-L1 levels in tumor-associated macrophages. In a mouse model with collagen-induced arthritis (CIA), SHH exhibited anti-inflammatory effects comparable to methotrexate (MTX), a first-line treatment for RA. Both the SHH and MTX groups had significantly lower arthritis scores and paw thickness compared to the CIA group. Additionally, SHH or MTX treatment effectively reduced elevated levels of anticollagen type II (CII) antibodies and proinflammatory cytokines (IL-1β, IL-6, and TNF-α). Histopathological analysis revealed that SHH and MTX treatments notably mitigated arthritic inflammation, synovial hyperplasia, and loss of articular cartilage and bone. Micro-CT scans showed reduced articular destruction in the SHH and MTX groups. These findings indicate that SHH treatment decreases PD-L1 levels in cancer cells and reduces the severity of CIA by exerting anti-inflammatory effects. Therefore, SHH holds promise as an I-O agent without side effects such as exacerbation of RA.
我们之前的研究突出了海兔水解物（SHH）的抗癌潜力，尤其是其在调节巨噬细胞极化以及通过抑制信号转导和转录激活因子3（STAT3）诱导肺癌细胞焦亡性死亡方面的作用。这些发现促使我们研究免疫肿瘤学（I-O）药物或佐剂的其他特性，如程序性细胞死亡蛋白1（PD-1）/程序性死亡配体1（PD-L1）抑制作用及其与类风湿性关节炎（RA）风险的关联，以探索SHH作为I-O药物或佐剂的潜力。在本研究中，我们研究了SHH对多种癌细胞类型中PD-L1水平的影响，并评估了其治疗I-O药物常见副作用RA的有效性。我们的结果显示，多种癌细胞系中的PD-L1水平显著降低，肿瘤相关巨噬细胞中的PD-1和PD-L1水平也有所下降。在胶原诱导性关节炎（CIA）小鼠模型中，SHH表现出与RA一线治疗药物甲氨蝶呤（MTX）相当的抗炎作用。与CIA组相比，SHH组和MTX组的关节炎评分和爪厚度均显著降低。此外，SHH或MTX治疗有效降低了抗II型胶原（CII）抗体和促炎细胞因子（IL-1β、IL-6和TNF-α）的升高水平。组织病理学分析显示，SHH和MTX治疗显著减轻了关节炎炎症、滑膜增生以及关节软骨和骨的丧失。显微CT扫描显示，SHH组和MTX组的关节破坏减少。这些发现表明，SHH治疗可降低癌细胞中的PD-L1水平，并通过发挥抗炎作用减轻CIA的严重程度。因此，SHH有望成为一种不会引发如RA加重等副作用的I-O药物。
