Sea Hare Hydrolysate Reduces PD‐L1 Levels in Cancer Cells and Mitigates Rheumatoid Arthritis Ina Collagen‐Induced Arthritis Mouse Model

Abstract

ABSTRACTOur 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.