Evaluación de la inmunogenicidad de células dendríticas pulsadas con diferentes formulaciones del antígeno con fines de inmunoterapia

ilustraciones, diagramas

Autores:: Alfaro Marenco, María Alejandra

Tipo de recurso:

Fecha de publicación:: 2024

Institución:: Universidad Nacional de Colombia

Repositorio:: Universidad Nacional de Colombia

Idioma:

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network_acronym_str	UNACIONAL2
network_name_str	Universidad Nacional de Colombia
repository_id_str
dc.title.spa.fl_str_mv	Evaluación de la inmunogenicidad de células dendríticas pulsadas con diferentes formulaciones del antígeno con fines de inmunoterapia
dc.title.translated.eng.fl_str_mv	Assessment of the immunogenicity of dendritic cells pulsed with different antigen formulations for immunotherapy purposes
title	Evaluación de la inmunogenicidad de células dendríticas pulsadas con diferentes formulaciones del antígeno con fines de inmunoterapia
spellingShingle	Evaluación de la inmunogenicidad de células dendríticas pulsadas con diferentes formulaciones del antígeno con fines de inmunoterapia 610 - Medicina y salud::616 - Enfermedades 610 - Medicina y salud::612 - Fisiología humana Inmunoterapia/métodos Vacunas contra el Cáncer Antígenos/uso terapéutico Immunotherapy/methods Cancer Vaccines Antigens/therapeutic use Linfocitos T CD8+ Muerte celular inmunogénica Citometría de flujo Células dendríticas derivadas de monocitos Formulaciones del antígeno Antígenos modelo Monocyte-derived dendritic cells Antigen formulations Model antigens CD8+ T cells Tumor cell lines immunogenic cell death Flow cytometry
title_short	Evaluación de la inmunogenicidad de células dendríticas pulsadas con diferentes formulaciones del antígeno con fines de inmunoterapia
title_full	Evaluación de la inmunogenicidad de células dendríticas pulsadas con diferentes formulaciones del antígeno con fines de inmunoterapia
title_fullStr	Evaluación de la inmunogenicidad de células dendríticas pulsadas con diferentes formulaciones del antígeno con fines de inmunoterapia
title_full_unstemmed	Evaluación de la inmunogenicidad de células dendríticas pulsadas con diferentes formulaciones del antígeno con fines de inmunoterapia
title_sort	Evaluación de la inmunogenicidad de células dendríticas pulsadas con diferentes formulaciones del antígeno con fines de inmunoterapia
dc.creator.fl_str_mv	Alfaro Marenco, María Alejandra
dc.contributor.advisor.spa.fl_str_mv	Bernal Estévez, David Andres Parra López, Carlos Alberto
dc.contributor.author.spa.fl_str_mv	Alfaro Marenco, María Alejandra
dc.subject.ddc.spa.fl_str_mv	610 - Medicina y salud::616 - Enfermedades 610 - Medicina y salud::612 - Fisiología humana
topic	610 - Medicina y salud::616 - Enfermedades 610 - Medicina y salud::612 - Fisiología humana Inmunoterapia/métodos Vacunas contra el Cáncer Antígenos/uso terapéutico Immunotherapy/methods Cancer Vaccines Antigens/therapeutic use Linfocitos T CD8+ Muerte celular inmunogénica Citometría de flujo Células dendríticas derivadas de monocitos Formulaciones del antígeno Antígenos modelo Monocyte-derived dendritic cells Antigen formulations Model antigens CD8+ T cells Tumor cell lines immunogenic cell death Flow cytometry
dc.subject.decs.spa.fl_str_mv	Inmunoterapia/métodos Vacunas contra el Cáncer Antígenos/uso terapéutico
dc.subject.decs.eng.fl_str_mv	Immunotherapy/methods Cancer Vaccines Antigens/therapeutic use
dc.subject.proposal.spa.fl_str_mv	Linfocitos T CD8+ Muerte celular inmunogénica Citometría de flujo Células dendríticas derivadas de monocitos Formulaciones del antígeno Antígenos modelo
dc.subject.proposal.eng.fl_str_mv	Monocyte-derived dendritic cells Antigen formulations Model antigens CD8+ T cells Tumor cell lines immunogenic cell death Flow cytometry
description	ilustraciones, diagramas
publishDate	2024
dc.date.accessioned.none.fl_str_mv	2024-06-04T21:14:14Z
dc.date.available.none.fl_str_mv	2024-06-04T21:14:14Z
dc.date.issued.none.fl_str_mv	2024
dc.type.spa.fl_str_mv	Trabajo de grado - Maestría
dc.type.driver.spa.fl_str_mv	info:eu-repo/semantics/masterThesis
dc.type.version.spa.fl_str_mv	info:eu-repo/semantics/acceptedVersion
dc.type.content.spa.fl_str_mv	Text
dc.type.redcol.spa.fl_str_mv	http://purl.org/redcol/resource_type/TM
status_str	acceptedVersion
dc.identifier.uri.none.fl_str_mv	https://repositorio.unal.edu.co/handle/unal/86203
dc.identifier.instname.spa.fl_str_mv	Universidad Nacional de Colombia
dc.identifier.reponame.spa.fl_str_mv	Repositorio Institucional Universidad Nacional de Colombia
dc.identifier.repourl.spa.fl_str_mv	https://repositorio.unal.edu.co/
url	https://repositorio.unal.edu.co/handle/unal/86203 https://repositorio.unal.edu.co/
identifier_str_mv	Universidad Nacional de Colombia Repositorio Institucional Universidad Nacional de Colombia
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spelling	Atribución-NoComercial-SinDerivadas 4.0 Internacionalhttp://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccesshttp://purl.org/coar/access_right/c_abf2Bernal Estévez, David Andreseebb2b477da688433ca45b907a57e850600Parra López, Carlos Alberto29924f3507fcedbca9501300464d5b61600Alfaro Marenco, María Alejandraf5d9273f2e9e206b32f62581a8fc68762024-06-04T21:14:14Z2024-06-04T21:14:14Z2024https://repositorio.unal.edu.co/handle/unal/86203Universidad Nacional de ColombiaRepositorio Institucional Universidad Nacional de Colombiahttps://repositorio.unal.edu.co/ilustraciones, diagramasLas vacunas basadas en células dendríticas (DCs) se han proyectado como una importante alternativa para la inmunoterapia del cáncer. Su diseño típicamente se fundamenta en la estimulación ex vivo de DCs derivadas de monocitos (MoDCs) utilizando diferentes formulaciones de antígenos y condiciones de maduración. Sin embargo, no hay consenso frente a la formulación óptima del antígeno a la hora de diseñar vacunas basadas en DCs. Por otro lado, se ha descrito que el estímulo de maduración en las MoDCs podría influir en su capacidad para presentar determinados formatos del antígeno. Por lo anterior, el presente trabajo se propuso explorar las implicaciones de diversas formulaciones del antígeno en el desarrollo de respuestas inmunes antitumorales por LT CD8+ cultivados con MoDCs tratadas bajo distintas condiciones. Para ello, se identificaron donantes sanos con LT CD8+ específicos contra epítopes modelo, utilizando el método de citometría basado en tetrámero. De forma paralela, se derivaron MoDCs que fueron estimuladas con dichos antígenos, bajo las formulaciones de péptido corto, péptido largo, proteína recombinante y célula tumoral, todas portadoras de la epítope inmunogénica de cada antígeno. Las MoDCs fueron maduradas empleando diferentes cocteles de citoquinas y se analizó la expresión diferencial de marcadores de maduración. Las líneas tumorales fueron tratadas con agentes quimioterapéuticos, a fin de determinar la expresión de calreticulina (CLR) como indicador de muerte celular inmunogénica (ICD) y su capacidad de favorecer su fagocitosis por MoDCs. Finalmente, se estableció un cocultivo de MoDCs y LT CD8+ autólogos antígeno-específicos o clones de LT CD8+ alogénicos específicos para las epítopes de interés; cuya respuesta efectora fue evaluada por medio de la producción de citoquinas y la expresión de marcadores de activación, agotamiento y memoria, utilizando citometría de flujo multiparamétrica. Se logró la expansión de LT CD8+ HLA-A02:01 tetrámero-positivos para una epítope viral y una tumoral, con los cuales se realizaron los ensayos de comparación entre formatos del antígeno y cocteles de maduración. Como se ha reportado clásicamente en la literatura, las formulaciones sencillas y directas basadas en péptidos promovieron respuestas robustas de activación y producción de citoquinas. Por el contrario, las formulaciones complejas como la proteína recombinante y las células tumorales tratadas mostraron respuestas efectoras menos evidentes. Los fenotipos de activación y agotamiento exhibieron una expresión dependiente principalmente del formato del antígeno utilizado, aunque se observó heterogeneidad entre los individuos. Adicionalmente, el marcador LAG-3 se vio influenciado por el coctel de maduración utilizado en las MoDCs. Por último, se logró inducir la expresión de CRL en las líneas tumorales tratadas y su fagocitosis por iDCs, aunque no se evidenció presentación cruzada del antígeno. Los resultados de este proyecto proporcionan información valiosa para el diseño de vacunas basadas en DCs y su potencial en inmunoterapia del cáncer. (Texto tomado de la fuente).Dendritic cell (DC)-based vaccines have been projected as a significant alternative for cancer immunotherapy. Typically, these vaccines are designed by stimulating monocyte-derived dendritic cells (MoDCs) ex vivo, employing diverse antigen formulations and maturation conditions. However, there is no consensus regarding the optimal antigen formulation when designing DC-based vaccines. On the other hand, it has been noted that the maturation stimulus in MoDCs could influence their ability to present specific antigen formats. This project aimed to investigate the effects of various antigen formulations on the development of anti-tumor immune responses by CD8+ T cells cultured with monocyte-derived dendritic cells (MoDCs) treated under different conditions. To achieve this, healthy donors with antigen-specific CD8+ T cell precursors for model epitopes were identified using tetramer-based flow cytometry. Simultaneously, MoDCs were derived and stimulated employing short peptide, long peptide, recombinant protein, or tumor cell formulations, all carrying the immunogenic epitope of each antigen. The MoDCs were matured using different cytokine cocktails, and the differential expression of maturation markers was analyzed. Tumor cell lines were treated with chemotherapeutic agents to determine calreticulin (CLR) expression as an indicator of immunogenic cell death (ICD). The ability of treated tumor cells to enhance phagocytosis by MoDCs was also assessed. Finally, a co-culture of autologous MoDCs and antigen-specific CD8+ T cells or allogeneic CD8+ T cell clones specific for the target epitopes was established. Their effector response was evaluated through cytokine production and the expression of activation, exhaustion, and memory markers, utilizing multiparametric flow cytometry. The expansion of HLA-A02:01 tetramer-positive CD8+ T cells was achieved for a viral and a tumor epitope. Using these, comparative assays were carried out between antigen formats and maturation cocktails. As classically reported in the literature, peptide-based formulations promoted robust activation and cytokine production responses. In contrast, more complex formulations such as recombinant protein and treated tumor cells exhibited less evident effector responses. The activation and exhaustion phenotypes showed expression primarily dependent on the antigen format used, although heterogeneity was observed among individuals. Additionally, LAG-3 was 13 influenced by the maturation cocktail used in MoDCs. Finally, the induction of calreticulin (CRL) expression in treated tumor cell lines and their phagocytosis by iDCs was achieved, although no evidence of antigen cross-presentation was observed. The findings of this project provide valuable insights for the design of DC-based vaccines and their potential in cancer immunotherapy.Fundación Salud de los AndesMaestríaMagíster en InmunologíaEstudio experimental in vitro156 páginasapplication/pdfUniversidad Nacional de ColombiaBogotá - Medicina - Maestría en InmunologíaFacultad de MedicinaBogotá, ColombiaUniversidad Nacional de Colombia - Sede Bogotá610 - Medicina y salud::616 - Enfermedades610 - Medicina y salud::612 - Fisiología humanaInmunoterapia/métodosVacunas contra el CáncerAntígenos/uso terapéuticoImmunotherapy/methodsCancer VaccinesAntigens/therapeutic useLinfocitos T CD8+Muerte celular inmunogénicaCitometría de flujoCélulas dendríticas derivadas de monocitosFormulaciones del antígenoAntígenos modeloMonocyte-derived dendritic cellsAntigen formulationsModel antigensCD8+ T cellsTumor cell linesimmunogenic cell deathFlow cytometryEvaluación de la inmunogenicidad de células dendríticas pulsadas con diferentes formulaciones del antígeno con fines de inmunoterapiaAssessment of the immunogenicity of dendritic cells pulsed with different antigen formulations for immunotherapy purposesTrabajo de grado - Maestríainfo:eu-repo/semantics/masterThesisinfo:eu-repo/semantics/acceptedVersionTexthttp://purl.org/redcol/resource_type/TMGierlich P, Lex V, Technau A, Keupp A, Morper L, Glunz A, et al. 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Oncoimmunology. 2014;3(9):e955691.Universidad Nacional de ColombiaMinisterio de Ciencia Tecnología e InnovaciónEstudiantesInvestigadoresLICENSElicense.txtlicense.txttext/plain; charset=utf-85879https://repositorio.unal.edu.co/bitstream/unal/86203/1/license.txteb34b1cf90b7e1103fc9dfd26be24b4aMD51ORIGINAL1026272802.2024.pdf1026272802.2024.pdfTesis de Maestría en Inmunologíaapplication/pdf3143082https://repositorio.unal.edu.co/bitstream/unal/86203/2/1026272802.2024.pdf6f54f9ece62a46be6843d08a1742e2a2MD52THUMBNAIL1026272802.2024.pdf.jpg1026272802.2024.pdf.jpgGenerated Thumbnailimage/jpeg4460https://repositorio.unal.edu.co/bitstream/unal/86203/3/1026272802.2024.pdf.jpg8aad89a8c243229ee65c6be73b9238c9MD53unal/86203oai:repositorio.unal.edu.co:unal/862032024-06-04 23:04:31.827Repositorio Institucional Universidad Nacional de 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