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Artículo

Restoration of antitumor immunity through anti-MICA antibodies elicited with a chimeric protein

Torres, Nicolas; Regge, María VictoriaIcon ; Secchiari, FlorenciaIcon ; Friedrich, Adrián DavidIcon ; Spallanzani, Raúl GermánIcon ; Raffo Iraolagoitia, Ximena LucíaIcon ; Nuñez, Sol YanelIcon ; Sierra, Jessica MarielIcon ; Ziblat, AndreaIcon ; Santilli, Maria CeciliaIcon ; Gilio, NicolasIcon ; Almada, EvangelinaIcon ; Lauché, Constanza ElenaIcon ; Pardo, Romina PaolaIcon ; Domaica, Carolina InesIcon ; Fuertes, Mercedes BeatrizIcon ; Madauss, Kevin Patrick; Hance, Kenneth W.; Gloger, Israel S.; Zylberman, VanesaIcon ; Goldbaum, Fernando AlbertoIcon ; Zwirner, Norberto WalterIcon
Fecha de publicación: 06/2020
Editorial: BMJ Publishing Group
Revista: Journal for ImmunoTherapy of Cancer
ISSN: 2051-1426
Idioma: Inglés
Tipo de recurso: Artículo publicado
Clasificación temática:
Inmunología

Resumen

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.
Palabras clave: TUMOR , MICA , CHIMERIC PROTEIN , IMMUNITY
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info:eu-repo/semantics/openAccess Excepto donde se diga explícitamente, este item se publica bajo la siguiente descripción: Creative Commons Attribution-NonCommercial 2.5 Unported (CC BY-NC 2.5)
Identificadores
URI: http://hdl.handle.net/11336/113252
URL: https://jitc.bmj.com/lookup/doi/10.1136/jitc-2019-000233
DOI: http://dx.doi.org/10.1136/jitc-2019-000233
Colecciones
Articulos(IBYME)
Articulos de INST.DE BIOLOGIA Y MEDICINA EXPERIMENTAL (I)
Citación
Torres, Nicolas; Regge, María Victoria; Secchiari, Florencia; Friedrich, Adrián David; Spallanzani, Raúl Germán; et al.; Restoration of antitumor immunity through anti-MICA antibodies elicited with a chimeric protein; BMJ Publishing Group; Journal for ImmunoTherapy of Cancer; 8; 1; 6-2020; 1-15
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