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Expression Analysis of Canine CMTM6 and CMTM4 as Potential Regulators of the PD-L1 Protein in Canine Cancers

Cancer is one of the most significant causes of death in dogs. Antibody drugs targeting the PD-1/PD-L1 axis represent a promising immunotherapy for both human and canine cancers. However, the regulation mechanisms of PD-L1 expression in canine cancers require further investigation to better understa...

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Autores principales: Takeuchi, Hiroto, Konnai, Satoru, Maekawa, Naoya, Minato, Erina, Ichikawa, Yoshiki, Kobayashi, Atsushi, Okagawa, Tomohiro, Murata, Shiro, Ohashi, Kazuhiko
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7300202/
https://www.ncbi.nlm.nih.gov/pubmed/32596272
http://dx.doi.org/10.3389/fvets.2020.00330
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author Takeuchi, Hiroto
Konnai, Satoru
Maekawa, Naoya
Minato, Erina
Ichikawa, Yoshiki
Kobayashi, Atsushi
Okagawa, Tomohiro
Murata, Shiro
Ohashi, Kazuhiko
author_facet Takeuchi, Hiroto
Konnai, Satoru
Maekawa, Naoya
Minato, Erina
Ichikawa, Yoshiki
Kobayashi, Atsushi
Okagawa, Tomohiro
Murata, Shiro
Ohashi, Kazuhiko
author_sort Takeuchi, Hiroto
collection PubMed
description Cancer is one of the most significant causes of death in dogs. Antibody drugs targeting the PD-1/PD-L1 axis represent a promising immunotherapy for both human and canine cancers. However, the regulation mechanisms of PD-L1 expression in canine cancers require further investigation to better understand the resistance mechanisms to anti-PD-L1 therapy. Recent reports have shown that CMTM6 and CMTM4 are critical regulators of PD-L1 protein expression in human cancer cells. By preventing PD-L1 from lysosome-mediated degradation, CMTM6 maintains PD-L1 expression on the cell surface. However, the literature has not reported on CMTM6 and CMTM4 in dogs, and their functions are completely unknown. To reveal a regulation mechanism of PD-L1 in canine cancers, this study firstly identified the gene sequences of CMTM6 and CMTM4. Then, the expression analysis of these proteins was performed by immunohistochemistry. Furthermore, the functions of CMTM6 and CMTM4 in regulating PD-L1 expression were examined by gene knockdown of CMTM6 and CMTM4. Canine CMTM6 and CMTM4 displayed high amino acid sequence identities compared with those of humans and mice. An immunohistochemical analysis using cross-reactive antibodies revealed that canine malignant melanoma and osteosarcoma express CMTM6, CMTM4, and PD-L1 simultaneously. Gene knockdown of CMTM6 and CMTM4 with RNA interference significantly reduced the cell surface expression of PD-L1 in a canine cell line. These results suggest that CMTM6 and CMTM4 are regulators of PD-L1 expression in canine cancers and could serve as potential therapeutic targets to enhance antitumor immunity.
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spelling pubmed-73002022020-06-26 Expression Analysis of Canine CMTM6 and CMTM4 as Potential Regulators of the PD-L1 Protein in Canine Cancers Takeuchi, Hiroto Konnai, Satoru Maekawa, Naoya Minato, Erina Ichikawa, Yoshiki Kobayashi, Atsushi Okagawa, Tomohiro Murata, Shiro Ohashi, Kazuhiko Front Vet Sci Veterinary Science Cancer is one of the most significant causes of death in dogs. Antibody drugs targeting the PD-1/PD-L1 axis represent a promising immunotherapy for both human and canine cancers. However, the regulation mechanisms of PD-L1 expression in canine cancers require further investigation to better understand the resistance mechanisms to anti-PD-L1 therapy. Recent reports have shown that CMTM6 and CMTM4 are critical regulators of PD-L1 protein expression in human cancer cells. By preventing PD-L1 from lysosome-mediated degradation, CMTM6 maintains PD-L1 expression on the cell surface. However, the literature has not reported on CMTM6 and CMTM4 in dogs, and their functions are completely unknown. To reveal a regulation mechanism of PD-L1 in canine cancers, this study firstly identified the gene sequences of CMTM6 and CMTM4. Then, the expression analysis of these proteins was performed by immunohistochemistry. Furthermore, the functions of CMTM6 and CMTM4 in regulating PD-L1 expression were examined by gene knockdown of CMTM6 and CMTM4. Canine CMTM6 and CMTM4 displayed high amino acid sequence identities compared with those of humans and mice. An immunohistochemical analysis using cross-reactive antibodies revealed that canine malignant melanoma and osteosarcoma express CMTM6, CMTM4, and PD-L1 simultaneously. Gene knockdown of CMTM6 and CMTM4 with RNA interference significantly reduced the cell surface expression of PD-L1 in a canine cell line. These results suggest that CMTM6 and CMTM4 are regulators of PD-L1 expression in canine cancers and could serve as potential therapeutic targets to enhance antitumor immunity. Frontiers Media S.A. 2020-06-11 /pmc/articles/PMC7300202/ /pubmed/32596272 http://dx.doi.org/10.3389/fvets.2020.00330 Text en Copyright © 2020 Takeuchi, Konnai, Maekawa, Minato, Ichikawa, Kobayashi, Okagawa, Murata and Ohashi. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Veterinary Science
Takeuchi, Hiroto
Konnai, Satoru
Maekawa, Naoya
Minato, Erina
Ichikawa, Yoshiki
Kobayashi, Atsushi
Okagawa, Tomohiro
Murata, Shiro
Ohashi, Kazuhiko
Expression Analysis of Canine CMTM6 and CMTM4 as Potential Regulators of the PD-L1 Protein in Canine Cancers
title Expression Analysis of Canine CMTM6 and CMTM4 as Potential Regulators of the PD-L1 Protein in Canine Cancers
title_full Expression Analysis of Canine CMTM6 and CMTM4 as Potential Regulators of the PD-L1 Protein in Canine Cancers
title_fullStr Expression Analysis of Canine CMTM6 and CMTM4 as Potential Regulators of the PD-L1 Protein in Canine Cancers
title_full_unstemmed Expression Analysis of Canine CMTM6 and CMTM4 as Potential Regulators of the PD-L1 Protein in Canine Cancers
title_short Expression Analysis of Canine CMTM6 and CMTM4 as Potential Regulators of the PD-L1 Protein in Canine Cancers
title_sort expression analysis of canine cmtm6 and cmtm4 as potential regulators of the pd-l1 protein in canine cancers
topic Veterinary Science
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7300202/
https://www.ncbi.nlm.nih.gov/pubmed/32596272
http://dx.doi.org/10.3389/fvets.2020.00330
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