Restoration of antitumor immunity through anti-MICA antibodies elicited with a chimeric protein
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Le résumé fourni par la source
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.
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Le contrôle bibliographique ouvert
DOI retrouvé dans Crossref DOI retrouvé ; titre concordant.
- Titre Crossref
- Restoration of antitumor immunity through anti-MICA antibodies elicited with a chimeric protein
- Date Crossref
- 01/06/2020
- Éditeur
- BMJ
- Type
- journal-article
Ce recoupement confirme des métadonnées liées au DOI. Il ne confirme ni la méthode ni les conclusions de l’étude, et il ne compte pas comme une seconde source scientifique indépendante.
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Experimental Medicine and Biology Institute pays non établi dans la noticeStructure de recherche
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GlaxoSmithKline (United States) pays non établi dans la noticeEntreprise
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GlaxoSmithKline (United Kingdom) pays non établi dans la noticeEntreprise
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Fundación Instituto Leloir pays non établi dans la noticeStructure de recherche
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Universidad de Buenos Aires pays non établi dans la noticeUniversité ou école supérieure
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Instituto de Biologia y Medicina Experimental Laboratorio de Fisiopatología de la Inmunidad Innata pays non établi dans la noticeStructure de recherche
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Inmunova pays non établi dans la noticeInstitution
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Collegeville GlaxoSmithKline pays non établi dans la noticeUniversité ou école supérieure
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Departamento de Química Biológica pays non établi dans la noticeInstitution
Experimental Medicine and Biology Institute, GlaxoSmithKline (United States) et GlaxoSmithKline (United Kingdom), avec 8 autres affiliations.
Une affiliation ne permet pas de déduire la nationalité d’un auteur.