A research group from the Graduate School of Veterinary Medicine (Hokkaido University), the Research Center for Zoonotic Diseases (Hokkaido University) and NICHe/Department of Antibody Drug Discovery (Graduate School of Medicine) has elucidated a novel mechanism of resistance acquisition. This mechanism reveals that prostaglandin E2 (PGE2), induced by treatment with the immune checkpoint inhibitor anti-PD-L1 antibody, attenuates the therapeutic efficacy of the antibody.
In recent years, immunotherapy, including immune checkpoint inhibitors, has gained attention in human medicine as the fourth treatment strategy for cancer patients. However, the response rate to immune checkpoint inhibitors remains limited to 20-30%, prompting active research into mechanisms of resistance acquisition and the development of combination therapies to enhance response rates. Our research group has previously reported, through studies using a model of lethal bovine infectious lymphoma (formerly known as bovine leukemia), that anti-PD-1/PD-L1 antibodies exhibit a certain therapeutic effect in BLV-infected cattle. Furthermore, we have demonstrated that combining a COX-2 inhibitor, which suppresses PGE2 production, with anti-PD-L1 antibodies enhances the therapeutic effect. However, the mechanism by which this combination enhances therapeutic efficacy remained unclear.
In this study, we first analyzed BLV-infected cattle treated with anti-PD-L1 antibodies and discovered that blood PGE2 concentrations increased following anti-PD-L1 antibody administration. In vitro analysis revealed that anti-PD-L1 antibody treatment enhances the production of TNF-α, an inflammatory cytokine, and that PGE2 production is induced via this TNF-α. Furthermore, we confirmed that PGE2 directly suppresses T cell activity via the EP4 receptor. Based on these findings, we verified the efficacy of combining anti-PD-L1 antibodies with EP4 inhibitors. This combination demonstrated immune-activating effects in both cattle and mice, and enhanced antitumor effects in a lymphoma mouse model. This groundbreaking research validated novel findings from immunotherapy studies in livestock using mouse models. Given the expected common mechanism across species, it holds promise as a novel immunotherapy applicable not only to livestock but also to humans.
The results were published in ImmunoHorizons on December 21, 2020.
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