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      Immune inhibitory function of bovine CTLA-4 and the effects of its blockade in IFN-γ production

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          Abstract

          Background

          Cytotoxic T-lymphocyte antigen 4 (CTLA-4) is known as an immune inhibitory receptor that is expressed on activated effector T cells and regulatory T cells. When CTLA-4 binds to CD80 or CD86, immunoinhibitory signals are transmitted to retain a homeostasis of the immune response. Recent studies have reported that CTLA-4 is upregulated in chronic infections and malignant neoplasms, contributing to host immune dysfunction. On the other hand, the blockade of CTLA-4 and CD80 or CD86 binding by antibody restores the immune response against these diseases. In a previous report, we indicated that the expression of CTLA-4 was closely associated with disease progression in cattle infected with the bovine leukemia virus (BLV). In this study, we established an anti-bovine CTLA-4 antibody to confirm its immune enhancing effect.

          Results

          Bovine CTLA-4-Ig binds to bovine CD80 and CD86 expressing cells. Additionally, CD80 and CD86 bind to CTLA-4 expressing cells in an expression-dependent manner. Bovine CTLA-4-Ig significantly inhibited interferon-gamma (IFN-γ) production from bovine peripheral blood mononuclear cells (PBMCs) activated by Staphylococcus enterotoxin B (SEB). An established specific monoclonal antibody (mAb) for bovine CTLA-4 specifically recognized only with bovine CTLA-4, not CD28, and the antibody blocked the binding of CTLA-4-Ig to both CD80 and CD86 in a dose-dependent manner. The bovine CTLA-4 mAb significantly restored the inhibited IFN-γ production from the CTLA-4-Ig treated PBMCs. In addition, the CTLA-4 mAb significantly enhanced IFN-γ production from CTLA-4 expressing PBMCs activated by SEB. Finally, we examined whether a CTLA-4 blockade by CTLA-4 mAb could restore the immune reaction during chronic infection; the blockade assay was performed using PBMCs from BLV-infected cattle. The CTLA-4 blockade enhanced IFN-γ production from the PBMCs in response to BLV-antigens.

          Conclusions

          Collectively, these results suggest that anti-bovine CTLA-4 antibody can reactivate lymphocyte functions and could be applied for a new therapy against refractory chronic diseases. Further investigation is required for future clinical applications.

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          Combined nivolumab and ipilimumab versus ipilimumab alone in patients with advanced melanoma: 2-year overall survival outcomes in a multicentre, randomised, controlled, phase 2 trial.

          F. Stephen Hodi, Jason Chesney, Anna C Pavlick … (2016)
          Results from phase 2 and 3 trials in patients with advanced melanoma have shown significant improvements in the proportion of patients achieving an objective response and prolonged progression-free survival with the combination of nivolumab (an anti-PD-1 antibody) plus ipilimumab (an anti-CTLA-4 antibody) compared with ipilimumab alone. We report 2-year overall survival data from a randomised controlled trial assessing this treatment in previously untreated advanced melanoma.
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            Expression of PD-L1 on Canine Tumor Cells and Enhancement of IFN-γ Production from Tumor-Infiltrating Cells by PD-L1 Blockade

            Naoya Maekawa, Satoru Konnai, Ryoyo Ikebuchi … (2014)
            Programmed death 1 (PD-1), an immunoinhibitory receptor, and programmed death ligand 1 (PD-L1), its ligand, together induce the “exhausted” status in antigen-specific lymphocytes and are thus involved in the immune evasion of tumor cells. In this study, canine PD-1 and PD-L1 were molecularly characterized, and their potential as therapeutic targets for canine tumors was discussed. The canine PD-1 and PD-L1 genes were conserved among canine breeds. Based on the sequence information obtained, the recombinant canine PD-1 and PD-L1 proteins were constructed; they were confirmed to bind each other. Antibovine PD-L1 monoclonal antibody effectively blocked the binding of recombinant PD-1 with PD-L1–expressing cells in a dose-dependent manner. Canine melanoma, mastocytoma, renal cell carcinoma, and other types of tumors examined expressed PD-L1, whereas some did not. Interestingly, anti-PD-L1 antibody treatment enhanced IFN-γ production from tumor-infiltrating cells. These results showed that the canine PD-1/PD-L1 pathway is also associated with T-cell exhaustion in canine tumors and that its blockade with antibody could be a new therapeutic strategy for canine tumors. Further investigations are needed to confirm the ability of anti-PD-L1 antibody to reactivate canine antitumor immunity in vivo, and its therapeutic potential has to be further discussed.
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              Therapeutic use of anti-CTLA-4 antibodies.

              Christian U. Blank, Alexander Enk (2015)
              Targeting CTLA-4 represents a new type of immunotherapeutic approach, namely immune checkpoint inhibition. Blockade of CTLA-4 by ipilimumab was the first strategy to achieve a significant clinical benefit for late-stage melanoma patients in two phase 3 trials. These results fueled the notion of immunotherapy being the breakthrough strategy for oncology in 2013. Subsequently, many trials have been set up to test various immune checkpoint modulators in malignancies, not only in melanoma. In this review, recent new ideas about the mechanism of action of CTLA-4 blockade, its current and future therapeutic use, and the intensive search for biomarkers for response will be discussed. Immune checkpoint blockade, targeting CTLA-4 and/or PD-1/PD-L1, is currently the most promising systemic therapeutic approach to achieve long-lasting responses or even cure in many types of cancer, not just in patients with melanoma.
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                Author and article information

                Contributors
                Kei Watari: k.watari@vetmed.hokudai.ac.jp
                Satoru Konnai:
                ORCID: http://orcid.org/0000-0002-3230-7109
                (81) 11 706 5216 , konnai@vetmed.hokudai.ac.jp
                Naoya Maekawa: maekawa@vetmed.hokudai.ac.jp
                Tomohiro Okagawa: okagawa@vetmed.hokudai.ac.jp
                Yasuhiko Suzuki: suzuki@czc.hokudai.ac.jp
                Shiro Murata: murata@vetmed.hokudai.ac.jp
                Kazuhiko Ohashi: okazu@vetmed.hokudai.ac.jp
                Journal
                Journal ID (nlm-ta): BMC Vet Res
                Journal ID (iso-abbrev): BMC Vet. Res
                Title: BMC Veterinary Research
                Publisher: BioMed Central (London )
                ISSN (Electronic): 1746-6148
                Publication date (Electronic): 29 October 2019
                Publication date PMC-release: 29 October 2019
                Publication date Collection: 2019
                Volume: 15
                Electronic Location Identifier: 380
                Affiliations
                [1 ]ISNI 0000 0001 2173 7691, GRID grid.39158.36, Department of Disease Control, Faculty of Veterinary Medicine, , Hokkaido University, ; Sapporo, Hokkaido 060-0818 Japan
                [2 ]ISNI 0000 0001 2173 7691, GRID grid.39158.36, Department of Advanced Pharmaceutics, Faculty of Veterinary Medicine, , Hokkaido University, ; Sapporo, 060-0818 Japan
                [3 ]ISNI 0000 0001 2173 7691, GRID grid.39158.36, Division of Bioresources, Research Center for Zoonosis Control, , Hokkaido University, ; Sapporo, 001-0020 Japan
                [4 ]ISNI 0000 0001 2173 7691, GRID grid.39158.36, Global Station for Zoonosis Control, , Global Institution for Collaborative Research and Education (GI-CoRE), Hokkaido University, ; Sapporo, 001-0020 Japan
                Author information
                http://orcid.org/0000-0002-3230-7109
                Article
                Publisher ID: 2082
                DOI: 10.1186/s12917-019-2082-7
                PMC ID: 6820917
                PubMed ID: 31665022
                SO-VID: ffcc0a75-6892-4659-aab8-a7c2cd3359ea
                Copyright © © The Author(s). 2019
                License:

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                Date received : 12 February 2019
                Date accepted : 6 September 2019
                Funding
                Funded by: Scientific Research from Japan Society for the Promotion of Science (JSPS)
                Funded by: Research Project for Improving Animal Disease Prevention Technologies to Combat Antimicrobial Resistance 2017-2021 FY, and by grants from the Project of the NARO
                Funded by: Bio-oriented Technology Research Advancement Institution (Research program on development of innovative technology
                Funded by: special scheme project on regional developing strategy
                Categories
                Subject: Research Article
                Custom metadata
                issue-copyright-statement © The Author(s) 2019

                ScienceOpen disciplines: Veterinary medicine
                Keywords: cattle,ctla-4,cd80,cd86,ifn-γ,blv
                Data availability:
                ScienceOpen disciplines: Veterinary medicine
                Keywords: cattle, ctla-4, cd80, cd86, ifn-γ, blv

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