Exploration of serum biomarkers in dogs with malignant melanoma receiving anti-PD-L1 therapy and potential of COX-2 inhibition for combination therapy
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 bioma...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2022-06-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-022-13484-8 |
| _version_ | 1818532581022367744 |
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| author | Naoya Maekawa Satoru Konnai Yumie Asano Yamato Sajiki Tatsuya Deguchi Tomohiro Okagawa Kei Watari Hiroto Takeuchi Satoshi Takagi Kenji Hosoya Sangho Kim Hiroshi Ohta Yukinari Kato Yasuhiko Suzuki Shiro Murata Kazuhiko Ohashi |
| author_facet | Naoya Maekawa Satoru Konnai Yumie Asano Yamato Sajiki Tatsuya Deguchi Tomohiro Okagawa Kei Watari Hiroto Takeuchi Satoshi Takagi Kenji Hosoya Sangho Kim Hiroshi Ohta Yukinari Kato Yasuhiko Suzuki Shiro Murata Kazuhiko Ohashi |
| author_sort | Naoya Maekawa |
| collection | DOAJ |
| description | 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 (PGE2), cytokines, chemokines, and growth factors were measured prior to treatment initiation. Among 12 factors tested, PGE2, 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 PGE2, 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 PGE2 confers resistance against anti-PD-L1 therapy through immunosuppression and thus is a candidate target for combination therapy. Indeed, PGE2 suppressed IL-2 and interferon (IFN)-γ production by stimulated canine peripheral blood mononuclear cells (PBMCs), while inhibition of PGE2 biosynthesis using the COX-2 inhibitor meloxicam in combination with c4G12 enhanced Th1 cytokine production by PBMCs. Thus, serum PGE2 may be predictive of c4G12 treatment response, and concomitant use of COX-2 inhibitors may enhance ICI antitumor efficacy. |
| first_indexed | 2024-12-11T17:47:24Z |
| format | Article |
| id | doaj.art-9195edeb9fe7415f92cb3f8d09b03d7b |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-12-11T17:47:24Z |
| publishDate | 2022-06-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-9195edeb9fe7415f92cb3f8d09b03d7b2022-12-22T00:56:19ZengNature PortfolioScientific Reports2045-23222022-06-0112111110.1038/s41598-022-13484-8Exploration of serum biomarkers in dogs with malignant melanoma receiving anti-PD-L1 therapy and potential of COX-2 inhibition for combination therapyNaoya Maekawa0Satoru Konnai1Yumie Asano2Yamato Sajiki3Tatsuya Deguchi4Tomohiro Okagawa5Kei Watari6Hiroto Takeuchi7Satoshi Takagi8Kenji Hosoya9Sangho Kim10Hiroshi Ohta11Yukinari Kato12Yasuhiko Suzuki13Shiro Murata14Kazuhiko Ohashi15Department of Advanced Pharmaceutics, Faculty of Veterinary Medicine, Hokkaido UniversityDepartment of Advanced Pharmaceutics, Faculty of Veterinary Medicine, Hokkaido UniversityDepartment of Disease Control, Faculty of Veterinary Medicine, Hokkaido UniversityDepartment of Disease Control, Faculty of Veterinary Medicine, Hokkaido UniversityVeterinary Teaching Hospital, Faculty of Veterinary Medicine, Hokkaido UniversityDepartment of Advanced Pharmaceutics, Faculty of Veterinary Medicine, Hokkaido UniversityDepartment of Disease Control, Faculty of Veterinary Medicine, Hokkaido UniversityDepartment of Disease Control, Faculty of Veterinary Medicine, Hokkaido UniversityVeterinary Teaching Hospital, Faculty of Veterinary Medicine, Hokkaido UniversityVeterinary Teaching Hospital, Faculty of Veterinary Medicine, Hokkaido UniversityVeterinary Teaching Hospital, Faculty of Veterinary Medicine, Hokkaido UniversityVeterinary Teaching Hospital, Faculty of Veterinary Medicine, Hokkaido UniversityDepartment of Antibody Drug Development, Tohoku University Graduate School of MedicineDepartment of Advanced Pharmaceutics, Faculty of Veterinary Medicine, Hokkaido UniversityDepartment of Advanced Pharmaceutics, Faculty of Veterinary Medicine, Hokkaido UniversityDepartment of Advanced Pharmaceutics, Faculty of Veterinary Medicine, Hokkaido UniversityAbstract 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 (PGE2), cytokines, chemokines, and growth factors were measured prior to treatment initiation. Among 12 factors tested, PGE2, 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 PGE2, 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 PGE2 confers resistance against anti-PD-L1 therapy through immunosuppression and thus is a candidate target for combination therapy. Indeed, PGE2 suppressed IL-2 and interferon (IFN)-γ production by stimulated canine peripheral blood mononuclear cells (PBMCs), while inhibition of PGE2 biosynthesis using the COX-2 inhibitor meloxicam in combination with c4G12 enhanced Th1 cytokine production by PBMCs. Thus, serum PGE2 may be predictive of c4G12 treatment response, and concomitant use of COX-2 inhibitors may enhance ICI antitumor efficacy.https://doi.org/10.1038/s41598-022-13484-8 |
| spellingShingle | Naoya Maekawa Satoru Konnai Yumie Asano Yamato Sajiki Tatsuya Deguchi Tomohiro Okagawa Kei Watari Hiroto Takeuchi Satoshi Takagi Kenji Hosoya Sangho Kim Hiroshi Ohta Yukinari Kato Yasuhiko Suzuki Shiro Murata Kazuhiko Ohashi Exploration of serum biomarkers in dogs with malignant melanoma receiving anti-PD-L1 therapy and potential of COX-2 inhibition for combination therapy Scientific Reports |
| title | Exploration of serum biomarkers in dogs with malignant melanoma receiving anti-PD-L1 therapy and potential of COX-2 inhibition for combination therapy |
| title_full | Exploration of serum biomarkers in dogs with malignant melanoma receiving anti-PD-L1 therapy and potential of COX-2 inhibition for combination therapy |
| title_fullStr | Exploration of serum biomarkers in dogs with malignant melanoma receiving anti-PD-L1 therapy and potential of COX-2 inhibition for combination therapy |
| title_full_unstemmed | Exploration of serum biomarkers in dogs with malignant melanoma receiving anti-PD-L1 therapy and potential of COX-2 inhibition for combination therapy |
| title_short | Exploration of serum biomarkers in dogs with malignant melanoma receiving anti-PD-L1 therapy and potential of COX-2 inhibition for combination therapy |
| title_sort | exploration of serum biomarkers in dogs with malignant melanoma receiving anti pd l1 therapy and potential of cox 2 inhibition for combination therapy |
| url | https://doi.org/10.1038/s41598-022-13484-8 |
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