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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

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 pre...

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Autores principales: Maekawa, Naoya, Konnai, Satoru, Asano, Yumie, Sajiki, Yamato, Deguchi, Tatsuya, Okagawa, Tomohiro, Watari, Kei, Takeuchi, Hiroto, Takagi, Satoshi, Hosoya, Kenji, Kim, Sangho, Ohta, Hiroshi, Kato, Yukinari, Suzuki, Yasuhiko, Murata, Shiro, Ohashi, Kazuhiko
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9166720/
https://www.ncbi.nlm.nih.gov/pubmed/35665759
http://dx.doi.org/10.1038/s41598-022-13484-8
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author Maekawa, Naoya
Konnai, Satoru
Asano, Yumie
Sajiki, Yamato
Deguchi, Tatsuya
Okagawa, Tomohiro
Watari, Kei
Takeuchi, Hiroto
Takagi, Satoshi
Hosoya, Kenji
Kim, Sangho
Ohta, Hiroshi
Kato, Yukinari
Suzuki, Yasuhiko
Murata, Shiro
Ohashi, Kazuhiko
author_facet Maekawa, Naoya
Konnai, Satoru
Asano, Yumie
Sajiki, Yamato
Deguchi, Tatsuya
Okagawa, Tomohiro
Watari, Kei
Takeuchi, Hiroto
Takagi, Satoshi
Hosoya, Kenji
Kim, Sangho
Ohta, Hiroshi
Kato, Yukinari
Suzuki, Yasuhiko
Murata, Shiro
Ohashi, Kazuhiko
author_sort Maekawa, Naoya
collection PubMed
description 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)-γ 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.
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spelling pubmed-91667202022-06-05 Exploration of serum biomarkers in dogs with malignant melanoma receiving anti-PD-L1 therapy and potential of COX-2 inhibition for combination therapy Maekawa, Naoya Konnai, Satoru Asano, Yumie Sajiki, Yamato Deguchi, Tatsuya Okagawa, Tomohiro Watari, Kei Takeuchi, Hiroto Takagi, Satoshi Hosoya, Kenji Kim, Sangho Ohta, Hiroshi Kato, Yukinari Suzuki, Yasuhiko Murata, Shiro Ohashi, Kazuhiko Sci Rep Article 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)-γ 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. Nature Publishing Group UK 2022-06-03 /pmc/articles/PMC9166720/ /pubmed/35665759 http://dx.doi.org/10.1038/s41598-022-13484-8 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Maekawa, Naoya
Konnai, Satoru
Asano, Yumie
Sajiki, Yamato
Deguchi, Tatsuya
Okagawa, Tomohiro
Watari, Kei
Takeuchi, Hiroto
Takagi, Satoshi
Hosoya, Kenji
Kim, Sangho
Ohta, Hiroshi
Kato, Yukinari
Suzuki, Yasuhiko
Murata, Shiro
Ohashi, Kazuhiko
Exploration of serum biomarkers in dogs with malignant melanoma receiving anti-PD-L1 therapy and potential of COX-2 inhibition for combination therapy
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
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9166720/
https://www.ncbi.nlm.nih.gov/pubmed/35665759
http://dx.doi.org/10.1038/s41598-022-13484-8
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