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Exploration of serum biomarkers in dogs with malignant melanoma receiving anti-PD-L1 therapy and potential of COX-2 inhibition for combination therapy

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Title: Exploration of serum biomarkers in dogs with malignant melanoma receiving anti-PD-L1 therapy and potential of COX-2 inhibition for combination therapy
Authors: Maekawa, Naoya Browse this author →KAKEN DB
Konnai, Satoru Browse this author →KAKEN DB
Asano, Yumie Browse this author
Sajiki, Yamato Browse this author
Deguchi, Tatsuya Browse this author
Okagawa, Tomohiro Browse this author →KAKEN DB
Watari, Kei Browse this author
Takeuchi, Hiroto Browse this author
Takagi, Satoshi Browse this author
Hosoya, Kenji Browse this author
Kim, Sangho Browse this author
Ohta, Hiroshi Browse this author
Kato, Yukinari Browse this author
Suzuki, Yasuhiko Browse this author →KAKEN DB
Murata, Shiro Browse this author →KAKEN DB
Ohashi, Kazuhiko Browse this author →KAKEN DB
Issue Date: 3-Jun-2022
Publisher: Nature Portfolio
Journal Title: Scientific reports
Volume: 12
Start Page: 9265
Publisher DOI: 10.1038/s41598-022-13484-8
Abstract: Immune checkpoint inhibitors (ICIs) such as anti-PD-L1 antibodies are widely used to treat human cancers, and growing evidence suggests that ICIs are promising treatments for canine malignancies. However, only some canine oral malignant melanoma (OMM) cases respond to ICIs. To explore biomarkers predictive of survival in dogs with pulmonary metastatic OMM receiving the anti-PD-L1 antibody c4G12 (n = 27), serum concentrations of prostaglandin E2 (PGE(2)), cytokines, chemokines, and growth factors were measured prior to treatment initiation. Among 12 factors tested, PGE(2), interleukin (IL)-12p40, IL-8, monocyte chemotactic protein-1 (MCP-1), and stem cell factor (SCF) were higher in OMM dogs compared to healthy dogs (n = 8). Further, lower baseline serum PGE(2), MCP-1, and vascular endothelial growth factor (VEGF)-A concentrations as well as higher IL-2, IL-12, and SCF concentrations predicted prolonged overall survival. These observations suggest that PGE(2) confers resistance against anti-PD-L1 therapy through immunosuppression and thus is a candidate target for combination therapy. Indeed, PGE(2) suppressed IL-2 and interferon (IFN)-gamma production by stimulated canine peripheral blood mononuclear cells (PBMCs), while inhibition of PGE(2) biosynthesis using the COX-2 inhibitor meloxicam in combination with c4G12 enhanced Th1 cytokine production by PBMCs. Thus, serum PGE(2) may be predictive of c4G12 treatment response, and concomitant use of COX-2 inhibitors may enhance ICI antitumor efficacy.
Type: article
Appears in Collections:獣医学院・獣医学研究院 (Graduate School of Veterinary Medicine / Faculty of Veterinary Medicine) > 雑誌発表論文等 (Peer-reviewed Journal Articles, etc)

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