Restoration of antitumor immunity through anti-MICA antibodies elicited with a chimeric protein
Background Natural killer and cytotoxic CD8+ T cells are major players during antitumor immunity. They express NKG2D, an activating receptor that promotes tumor elimination through recognition of the MHC class I chain-related proteins A and B (MICA and MICB). Both molecules are overexpressed on a gr...
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BMJ Publishing Group
2020-05-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/8/1/e000233.full |
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| author | Kenneth W Hance Nicolas Torres María Victoria Regge Florencia Secchiari Adrián David Friedrich Raúl Germán Spallanzani Ximena Lucía Raffo Iraolagoitia Sol Yanel Núñez Jessica Mariel Sierra Andrea Ziblat María Cecilia Santilli Nicolás Gilio Evangelina Almada Constanza Lauche Romina Pardo Carolina Inés Domaica Mercedes Beatriz Fuertes Kevin Patrick Madauss Israel S Gloger Vanesa Zylberman Fernando Alberto Goldbaum Norberto Walter Zwirner |
| author_facet | Kenneth W Hance Nicolas Torres María Victoria Regge Florencia Secchiari Adrián David Friedrich Raúl Germán Spallanzani Ximena Lucía Raffo Iraolagoitia Sol Yanel Núñez Jessica Mariel Sierra Andrea Ziblat María Cecilia Santilli Nicolás Gilio Evangelina Almada Constanza Lauche Romina Pardo Carolina Inés Domaica Mercedes Beatriz Fuertes Kevin Patrick Madauss Israel S Gloger Vanesa Zylberman Fernando Alberto Goldbaum Norberto Walter Zwirner |
| author_sort | Kenneth W Hance |
| collection | DOAJ |
| description | Background Natural killer and cytotoxic CD8+ T cells are major players during antitumor immunity. They express NKG2D, an activating receptor that promotes tumor elimination through recognition of the MHC class I chain-related proteins A and B (MICA and MICB). Both molecules are overexpressed on a great variety of tumors from different tissues, making them attractive targets for immunotherapy. However, tumors shed MICA and MICB, and the soluble forms of both (sMICA and sMICB) mediate tumor-immune escape. Some reports indicate that anti-MICA antibodies (Ab) can promote the restoration of antitumor immunity through the induction of direct antitumor effects (antibody-dependent cell-mediated cytotoxicity, ADCC) and scavenging of sMICA. Therefore, we reasoned that an active induction of anti-MICA Ab with an immunogenic protein might represent a novel therapeutic and prophylactic alternative to restore antitumor immunity.Methods We generated a highly immunogenic chimeric protein (BLS-MICA) consisting of human MICA fused to the lumazine synthase from Brucella spp (BLS) and used it to generate anti-MICA polyclonal Ab (pAb) and to investigate if these anti-MICA Ab can reinstate antitumor immunity in mice using two different mouse tumors engineered to express MICA. We also explored the underlying mechanisms of this expected therapeutic effect.Results Immunization with BLS-MICA and administration of anti-MICA pAb elicited by BLS-MICA significantly delayed the growth of MICA-expressing mouse tumors but not of control tumors. The therapeutic effect of immunization with BLS-MICA included scavenging of sMICA and the anti-MICA Ab-mediated ADCC, promoting heightened intratumoral M1/proinflammatory macrophage and antigen-experienced CD8+ T cell recruitment.Conclusions Immunization with the chimeric protein BLS-MICA constitutes a useful way to actively induce therapeutic anti-MICA pAb that resulted in a reprogramming of the antitumor immune response towards an antitumoral/proinflammatory phenotype. Hence, the BLS-MICA chimeric protein constitutes a novel antitumor vaccine of potential application in patients with MICA-expressing tumors. |
| format | Article |
| id | doaj-art-60794d6d6f5348769085d3ffeeb174f9 |
| institution | Kabale University |
| issn | 2051-1426 |
| language | English |
| publishDate | 2020-05-01 |
| publisher | BMJ Publishing Group |
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| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-60794d6d6f5348769085d3ffeeb174f92024-11-09T11:20:08ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262020-05-018110.1136/jitc-2019-000233Restoration of antitumor immunity through anti-MICA antibodies elicited with a chimeric proteinKenneth W Hance0Nicolas Torres1María Victoria Regge2Florencia Secchiari3Adrián David Friedrich4Raúl Germán Spallanzani5Ximena Lucía Raffo Iraolagoitia6Sol Yanel Núñez7Jessica Mariel Sierra8Andrea Ziblat9María Cecilia Santilli10Nicolás Gilio11Evangelina Almada12Constanza Lauche13Romina Pardo14Carolina Inés Domaica15Mercedes Beatriz Fuertes16Kevin Patrick Madauss17Israel S Gloger18Vanesa Zylberman19Fernando Alberto Goldbaum20Norberto Walter Zwirner21Aff2 grid.481568.6EMD Serono Research & Development Institute, Inc Billerica MA USA1 Laboratorio de Fisiopatología de la Inmunidad Innata, Instituto de Biologia y Medicina Experimental, Buenos Aires, Argentina1 Laboratorio de Fisiopatología de la Inmunidad Innata, Instituto de Biologia y Medicina Experimental, Buenos Aires, Argentina1 Laboratorio de Fisiopatología de la Inmunidad Innata, Instituto de Biologia y Medicina Experimental, Buenos Aires, Argentina1 Laboratorio de Fisiopatología de la Inmunidad Innata, Instituto de Biologia y Medicina Experimental, Buenos Aires, Argentina1 Laboratorio de Fisiopatología de la Inmunidad Innata, Instituto de Biologia y Medicina Experimental, Buenos Aires, Argentina1 Laboratorio de Fisiopatología de la Inmunidad Innata, Instituto de Biologia y Medicina Experimental, Buenos Aires, Argentina1 Laboratorio de Fisiopatología de la Inmunidad Innata, Instituto de Biologia y Medicina Experimental, Buenos Aires, Argentina1 Laboratorio de Fisiopatología de la Inmunidad Innata, Instituto de Biologia y Medicina Experimental, Buenos Aires, Argentina1 Laboratorio de Fisiopatología de la Inmunidad Innata, Instituto de Biologia y Medicina Experimental, Buenos Aires, Argentina1 Laboratorio de Fisiopatología de la Inmunidad Innata, Instituto de Biologia y Medicina Experimental, Buenos Aires, Argentina1 Laboratorio de Fisiopatología de la Inmunidad Innata, Instituto de Biologia y Medicina Experimental, Buenos Aires, Argentina1 Laboratorio de Fisiopatología de la Inmunidad Innata, Instituto de Biologia y Medicina Experimental, Buenos Aires, Argentina2 Inmunova, Buenos Aires, Argentina2 Inmunova, Buenos Aires, Argentina1 Laboratorio de Fisiopatología de la Inmunidad Innata, Instituto de Biologia y Medicina Experimental, Buenos Aires, Argentina1 Laboratorio de Fisiopatología de la Inmunidad Innata, Instituto de Biologia y Medicina Experimental, Buenos Aires, Argentina3 Trust in Science, Global Health R&D, GlaxoSmithKline, Collegeville, PA, United States5 Trust in Science, Global Health R&D, GlaxoSmithKline, Stevenage, United Kingdom2 Inmunova, Buenos Aires, Argentina2 Inmunova, Buenos Aires, Argentina1 Laboratorio de Fisiopatología de la Inmunidad Innata, Instituto de Biologia y Medicina Experimental, Buenos Aires, ArgentinaBackground Natural killer and cytotoxic CD8+ T cells are major players during antitumor immunity. They express NKG2D, an activating receptor that promotes tumor elimination through recognition of the MHC class I chain-related proteins A and B (MICA and MICB). Both molecules are overexpressed on a great variety of tumors from different tissues, making them attractive targets for immunotherapy. However, tumors shed MICA and MICB, and the soluble forms of both (sMICA and sMICB) mediate tumor-immune escape. Some reports indicate that anti-MICA antibodies (Ab) can promote the restoration of antitumor immunity through the induction of direct antitumor effects (antibody-dependent cell-mediated cytotoxicity, ADCC) and scavenging of sMICA. Therefore, we reasoned that an active induction of anti-MICA Ab with an immunogenic protein might represent a novel therapeutic and prophylactic alternative to restore antitumor immunity.Methods We generated a highly immunogenic chimeric protein (BLS-MICA) consisting of human MICA fused to the lumazine synthase from Brucella spp (BLS) and used it to generate anti-MICA polyclonal Ab (pAb) and to investigate if these anti-MICA Ab can reinstate antitumor immunity in mice using two different mouse tumors engineered to express MICA. We also explored the underlying mechanisms of this expected therapeutic effect.Results Immunization with BLS-MICA and administration of anti-MICA pAb elicited by BLS-MICA significantly delayed the growth of MICA-expressing mouse tumors but not of control tumors. The therapeutic effect of immunization with BLS-MICA included scavenging of sMICA and the anti-MICA Ab-mediated ADCC, promoting heightened intratumoral M1/proinflammatory macrophage and antigen-experienced CD8+ T cell recruitment.Conclusions Immunization with the chimeric protein BLS-MICA constitutes a useful way to actively induce therapeutic anti-MICA pAb that resulted in a reprogramming of the antitumor immune response towards an antitumoral/proinflammatory phenotype. Hence, the BLS-MICA chimeric protein constitutes a novel antitumor vaccine of potential application in patients with MICA-expressing tumors.https://jitc.bmj.com/content/8/1/e000233.full |
| spellingShingle | Kenneth W Hance Nicolas Torres María Victoria Regge Florencia Secchiari Adrián David Friedrich Raúl Germán Spallanzani Ximena Lucía Raffo Iraolagoitia Sol Yanel Núñez Jessica Mariel Sierra Andrea Ziblat María Cecilia Santilli Nicolás Gilio Evangelina Almada Constanza Lauche Romina Pardo Carolina Inés Domaica Mercedes Beatriz Fuertes Kevin Patrick Madauss Israel S Gloger Vanesa Zylberman Fernando Alberto Goldbaum Norberto Walter Zwirner Restoration of antitumor immunity through anti-MICA antibodies elicited with a chimeric protein Journal for ImmunoTherapy of Cancer |
| title | Restoration of antitumor immunity through anti-MICA antibodies elicited with a chimeric protein |
| title_full | Restoration of antitumor immunity through anti-MICA antibodies elicited with a chimeric protein |
| title_fullStr | Restoration of antitumor immunity through anti-MICA antibodies elicited with a chimeric protein |
| title_full_unstemmed | Restoration of antitumor immunity through anti-MICA antibodies elicited with a chimeric protein |
| title_short | Restoration of antitumor immunity through anti-MICA antibodies elicited with a chimeric protein |
| title_sort | restoration of antitumor immunity through anti mica antibodies elicited with a chimeric protein |
| url | https://jitc.bmj.com/content/8/1/e000233.full |
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