Macrophages Impair TLR9 Agonist Antitumor Activity through Interacting with the Anti-PD-1 Antibody Fc Domain
Background. A combination of TLR9 agonists and an anti-PD-1 antibody has been reported to be effective in immunocompetent mice but the role of innate immunity has not yet been completely elucidated. Therefore, we investigated the contribution of the innate immune system to this combinatorial immunot...
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| Format: | Article |
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MDPI AG
2021-08-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/13/16/4081 |
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| author | Simone Camelliti Valentino Le Noci Francesca Bianchi Chiara Storti Francesca Arnaboldi Alessandra Cataldo Serena Indino Elena Jachetti Mariangela Figini Mario Paolo Colombo Andrea Balsari Nicoletta Gagliano Elda Tagliabue Lucia Sfondrini Michele Sommariva |
| author_facet | Simone Camelliti Valentino Le Noci Francesca Bianchi Chiara Storti Francesca Arnaboldi Alessandra Cataldo Serena Indino Elena Jachetti Mariangela Figini Mario Paolo Colombo Andrea Balsari Nicoletta Gagliano Elda Tagliabue Lucia Sfondrini Michele Sommariva |
| author_sort | Simone Camelliti |
| collection | DOAJ |
| description | Background. A combination of TLR9 agonists and an anti-PD-1 antibody has been reported to be effective in immunocompetent mice but the role of innate immunity has not yet been completely elucidated. Therefore, we investigated the contribution of the innate immune system to this combinatorial immunotherapeutic regimens using an immunodeficient mouse model in which the effector functions of innate immunity can clearly emerge without any interference from T lymphocytes. Methods. Athymic mice xenografted with IGROV-1 human ovarian cells, reported to be sensitive to TLR9 agonist therapy, were treated with cytosine–guanine (CpG)-oligodeoxynucleotides (ODNs), an anti-PD-1 antibody or their combination. Results. We found that PD-1 blockade dampened CpG-ODN antitumor activity. In vitro studies indicated that the interaction between the anti-PD-1 antibody fragment crystallizable (Fc) domain and macrophage Fc receptors caused these immune cells to acquire an immunoregulatory phenotype, contributing to a decrease in the efficacy of CpG-ODNs. Accordingly, in vivo macrophage depletion abrogated the detrimental effect exerted by the anti-PD-1 antibody. Conclusion. Our data suggest that if TLR signaling is active in macrophages, coadministration of an anti-PD-1 antibody can reprogram these immune cells towards a polarization state able to negatively affect the immune response and eventually promote tumor growth. |
| first_indexed | 2024-03-10T08:57:13Z |
| format | Article |
| id | doaj.art-25bd4cea22204f4b848e2bb8f7d4d882 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T08:57:13Z |
| publishDate | 2021-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-25bd4cea22204f4b848e2bb8f7d4d8822023-11-22T07:03:28ZengMDPI AGCancers2072-66942021-08-011316408110.3390/cancers13164081Macrophages Impair TLR9 Agonist Antitumor Activity through Interacting with the Anti-PD-1 Antibody Fc DomainSimone Camelliti0Valentino Le Noci1Francesca Bianchi2Chiara Storti3Francesca Arnaboldi4Alessandra Cataldo5Serena Indino6Elena Jachetti7Mariangela Figini8Mario Paolo Colombo9Andrea Balsari10Nicoletta Gagliano11Elda Tagliabue12Lucia Sfondrini13Michele Sommariva14Dipartimento di Scienze Biomediche per la Salute, Università degli Studi di Milano, Via Mangiagalli 31, 20133 Milan, ItalyDipartimento di Scienze Biomediche per la Salute, Università degli Studi di Milano, Via Mangiagalli 31, 20133 Milan, ItalyDipartimento di Scienze Biomediche per la Salute, Università degli Studi di Milano, Via Mangiagalli 31, 20133 Milan, ItalyDipartimento di Scienze Biomediche per la Salute, Università degli Studi di Milano, Via Mangiagalli 31, 20133 Milan, ItalyDipartimento di Scienze Biomediche per la Salute, Università degli Studi di Milano, Via Mangiagalli 31, 20133 Milan, ItalyMolecular Targeting Unit, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Amadeo 42, 20133 Milan, ItalyDipartimento di Scienze Biomediche per la Salute, Università degli Studi di Milano, Via Mangiagalli 31, 20133 Milan, ItalyMolecular Immunology Unit, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Amadeo 42, 20133 Milan, ItalyDipartimento di Ricerca Applicata e Sviluppo Tecnologico, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Amadeo 42, 20133 Milan, ItalyMolecular Immunology Unit, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Amadeo 42, 20133 Milan, ItalyDipartimento di Scienze Biomediche per la Salute, Università degli Studi di Milano, Via Mangiagalli 31, 20133 Milan, ItalyDipartimento di Scienze Biomediche per la Salute, Università degli Studi di Milano, Via Mangiagalli 31, 20133 Milan, ItalyMolecular Targeting Unit, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Amadeo 42, 20133 Milan, ItalyDipartimento di Scienze Biomediche per la Salute, Università degli Studi di Milano, Via Mangiagalli 31, 20133 Milan, ItalyDipartimento di Scienze Biomediche per la Salute, Università degli Studi di Milano, Via Mangiagalli 31, 20133 Milan, ItalyBackground. A combination of TLR9 agonists and an anti-PD-1 antibody has been reported to be effective in immunocompetent mice but the role of innate immunity has not yet been completely elucidated. Therefore, we investigated the contribution of the innate immune system to this combinatorial immunotherapeutic regimens using an immunodeficient mouse model in which the effector functions of innate immunity can clearly emerge without any interference from T lymphocytes. Methods. Athymic mice xenografted with IGROV-1 human ovarian cells, reported to be sensitive to TLR9 agonist therapy, were treated with cytosine–guanine (CpG)-oligodeoxynucleotides (ODNs), an anti-PD-1 antibody or their combination. Results. We found that PD-1 blockade dampened CpG-ODN antitumor activity. In vitro studies indicated that the interaction between the anti-PD-1 antibody fragment crystallizable (Fc) domain and macrophage Fc receptors caused these immune cells to acquire an immunoregulatory phenotype, contributing to a decrease in the efficacy of CpG-ODNs. Accordingly, in vivo macrophage depletion abrogated the detrimental effect exerted by the anti-PD-1 antibody. Conclusion. Our data suggest that if TLR signaling is active in macrophages, coadministration of an anti-PD-1 antibody can reprogram these immune cells towards a polarization state able to negatively affect the immune response and eventually promote tumor growth.https://www.mdpi.com/2072-6694/13/16/4081ovarian cancerToll-like receptor 9 (TLR9)CpG oligodeoxynucleotides (CpG-ODNs)programmed cell death 1 (PD-1)macrophagesFc receptors |
| spellingShingle | Simone Camelliti Valentino Le Noci Francesca Bianchi Chiara Storti Francesca Arnaboldi Alessandra Cataldo Serena Indino Elena Jachetti Mariangela Figini Mario Paolo Colombo Andrea Balsari Nicoletta Gagliano Elda Tagliabue Lucia Sfondrini Michele Sommariva Macrophages Impair TLR9 Agonist Antitumor Activity through Interacting with the Anti-PD-1 Antibody Fc Domain Cancers ovarian cancer Toll-like receptor 9 (TLR9) CpG oligodeoxynucleotides (CpG-ODNs) programmed cell death 1 (PD-1) macrophages Fc receptors |
| title | Macrophages Impair TLR9 Agonist Antitumor Activity through Interacting with the Anti-PD-1 Antibody Fc Domain |
| title_full | Macrophages Impair TLR9 Agonist Antitumor Activity through Interacting with the Anti-PD-1 Antibody Fc Domain |
| title_fullStr | Macrophages Impair TLR9 Agonist Antitumor Activity through Interacting with the Anti-PD-1 Antibody Fc Domain |
| title_full_unstemmed | Macrophages Impair TLR9 Agonist Antitumor Activity through Interacting with the Anti-PD-1 Antibody Fc Domain |
| title_short | Macrophages Impair TLR9 Agonist Antitumor Activity through Interacting with the Anti-PD-1 Antibody Fc Domain |
| title_sort | macrophages impair tlr9 agonist antitumor activity through interacting with the anti pd 1 antibody fc domain |
| topic | ovarian cancer Toll-like receptor 9 (TLR9) CpG oligodeoxynucleotides (CpG-ODNs) programmed cell death 1 (PD-1) macrophages Fc receptors |
| url | https://www.mdpi.com/2072-6694/13/16/4081 |
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