Caracterización del infiltrado inmune tumoral en pacientes con cáncer de mama

ilustraciones, fotografía a color

Autores:
Llano León, Manuela
Tipo de recurso:
Fecha de publicación:
2023
Institución:
Universidad Nacional de Colombia
Repositorio:
Universidad Nacional de Colombia
Idioma:
spa
OAI Identifier:
oai:repositorio.unal.edu.co:unal/83670
Acceso en línea:
https://repositorio.unal.edu.co/handle/unal/83670
https://repositorio.unal.edu.co/
Palabra clave:
Neoplasias de la Mama
Acciones Terapéuticas
Microambiente inmune tumoral
Cáncer de mama
Inmunovigilancia
Quimioterapia neoadyuvante
Tumor immune microenvironment
Immunosurveillance
Neoadjuvant chemotherapy
Breast Cancer
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openAccess
License
Reconocimiento 4.0 Internacional
id UNACIONAL2_edcbc46139a8d1058e493695a92c4063
oai_identifier_str oai:repositorio.unal.edu.co:unal/83670
network_acronym_str UNACIONAL2
network_name_str Universidad Nacional de Colombia
repository_id_str
dc.title.spa.fl_str_mv Caracterización del infiltrado inmune tumoral en pacientes con cáncer de mama
dc.title.translated.eng.fl_str_mv Tumor immune infiltrate characterization in breast cancer patients
title Caracterización del infiltrado inmune tumoral en pacientes con cáncer de mama
spellingShingle Caracterización del infiltrado inmune tumoral en pacientes con cáncer de mama
Neoplasias de la Mama
Acciones Terapéuticas
Microambiente inmune tumoral
Cáncer de mama
Inmunovigilancia
Quimioterapia neoadyuvante
Tumor immune microenvironment
Immunosurveillance
Neoadjuvant chemotherapy
Breast Cancer
title_short Caracterización del infiltrado inmune tumoral en pacientes con cáncer de mama
title_full Caracterización del infiltrado inmune tumoral en pacientes con cáncer de mama
title_fullStr Caracterización del infiltrado inmune tumoral en pacientes con cáncer de mama
title_full_unstemmed Caracterización del infiltrado inmune tumoral en pacientes con cáncer de mama
title_sort Caracterización del infiltrado inmune tumoral en pacientes con cáncer de mama
dc.creator.fl_str_mv Llano León, Manuela
dc.contributor.advisor.none.fl_str_mv Parra López, Carlos Alberto
dc.contributor.author.none.fl_str_mv Llano León, Manuela
dc.contributor.researchgroup.spa.fl_str_mv Laboratorio de Inmunología y Medicina Traslacional
dc.contributor.orcid.spa.fl_str_mv https://orcid.org/0000-0002-6436-1556
dc.contributor.cvlac.spa.fl_str_mv https://scienti.minciencias.gov.co/cvlac/visualizador/generarCurriculoCv.do?cod_rh=0000126438
dc.subject.decs.spa.fl_str_mv Neoplasias de la Mama
Acciones Terapéuticas
topic Neoplasias de la Mama
Acciones Terapéuticas
Microambiente inmune tumoral
Cáncer de mama
Inmunovigilancia
Quimioterapia neoadyuvante
Tumor immune microenvironment
Immunosurveillance
Neoadjuvant chemotherapy
Breast Cancer
dc.subject.proposal.spa.fl_str_mv Microambiente inmune tumoral
Cáncer de mama
Inmunovigilancia
Quimioterapia neoadyuvante
dc.subject.proposal.eng.fl_str_mv Tumor immune microenvironment
Immunosurveillance
Neoadjuvant chemotherapy
Breast Cancer
description ilustraciones, fotografía a color
publishDate 2023
dc.date.accessioned.none.fl_str_mv 2023-03-29T16:58:50Z
dc.date.available.none.fl_str_mv 2023-03-29T16:58:50Z
dc.date.issued.none.fl_str_mv 2023-03-27
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/83670
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/83670
https://repositorio.unal.edu.co/
identifier_str_mv Universidad Nacional de Colombia
Repositorio Institucional Universidad Nacional de Colombia
dc.language.iso.spa.fl_str_mv spa
language spa
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spelling Reconocimiento 4.0 Internacionalhttp://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccesshttp://purl.org/coar/access_right/c_abf2Parra López, Carlos Alberto72ac583cfa47cd3a2fb760ecf10befccLlano León, Manuela84e4b041c15cc20c4b7520f7e498a914Laboratorio de Inmunología y Medicina Traslacionalhttps://orcid.org/0000-0002-6436-1556https://scienti.minciencias.gov.co/cvlac/visualizador/generarCurriculoCv.do?cod_rh=00001264382023-03-29T16:58:50Z2023-03-29T16:58:50Z2023-03-27https://repositorio.unal.edu.co/handle/unal/83670Universidad Nacional de ColombiaRepositorio Institucional Universidad Nacional de Colombiahttps://repositorio.unal.edu.co/ilustraciones, fotografía a colorEn Colombia, el cáncer de mama es el tipo de cáncer con mayor incidencia y prevalencia en la mujer, ocupando el tercer puesto en mortalidad a nivel nacional. La vigilancia del tumor en pacientes con cáncer de mama por las células del sistema inmune -inmunovigilancia- es importante para el control del desarrollo tumoral. Reportes en la literatura sugieren que el esquema de quimioterapia neoadyuvante con Doxorrubicina y Ciclofosfamida induce un tipo especial de muerte en las células tumorales conocida como muerte celular inmunogénica, activando las poblaciones inmunes intratumorales y favoreciendo la inmunovigilancia de este tumor, lo cual, probablemente contribuye a una mejor respuesta clínica al tratamiento antitumoral. Estudios demuestran que el microambiente tumoral es un factor determinante en el pronóstico de los pacientes con cáncer. Aunque en los tumores de cáncer de mama se ha descrito la importancia de analizar el infiltrado inmune para evaluar la presencia de poblaciones efectoras y de poblaciones reguladoras, este tipo de análisis para proponer marcadores pronósticos de evolución y de respuesta al tratamiento han sido limitados. En este trabajo estandarizamos una metodología de inmunohistoquímica secuencial sobre lámina única para la caracterización de poblaciones del sistema inmune innato y adaptativo como: i) Leucocitos totales CD45+ ii) Macrófagos CD68+ III). Linfocitos B CD20+ iv). Linfocitos T totales CD3+ y v). Linfocitos T Citotóxicos CD8+, con relación a las células tumorales evaluadas con el marcador Pankeratinas. Se demostró que esta técnica representa una alternativa costo-efectiva para mapear el microambiente tumoral, que permite monitorear la infiltración de estas poblaciones antes y después de la quimioterapia y que en este trabajo nos permitió evidenciar un aumento significativo de la infiltración de células CD45 positivas después del tratamiento neoadyuvante. Adicionalmente, utilizamos la herramienta CIBERSORTx para medir 22 subpoblaciones inmunes, con datos disponibles en el Genome European Archive por medio del análisis del transcriptoma tumoral. Se encontraron cambios significativos en diferentes poblaciones: primero, un aumento después de un ciclo de quimioterapia de las fracciones relativas de Linfocitos T CD8, Linfocitos T CD4 quiescentes y de Linfocitos T reguladores, las cuales disminuyeron al terminar el esquema de neoadyuvancia. Segundo, las fracciones relativas de Linfocitos B de memoria, Macrófagos M1, y Linfocitos T Foliculares disminuyeron después de un ciclo y al final del tratamiento. Por último, las Células Dendríticas activadas, los Macrófagos M2 y los Mastocitos aumentaron después de un ciclo, y al finalizar el tratamiento. Por otra parte, se realizó una revisión sistemática que nos permitió incluir 32 artículos para una síntesis cualitativa de la evidencia y 9 artículos, para una síntesis cuantitativa por medio de meta-análisis, en los cuales encontramos una disminución significativa de la infiltración de TILs (T Infiltrating Lymphocytes) evaluados morfológicamente en láminas de hematoxilina & eosina y del marcador FoxP3 medido por inmunohistoquímica tradicional, lo que sugiere una disminución de las poblaciones de linfocitos T reguladores en respuesta a la NAC (neoadyuvant chemotherapy). Las poblaciones de Linfocitos T totales CD3+, Linfocitos T colaboradores CD4+ y Linfocitos T citotóxicos CD8+ no cambiaron significativamente en respuesta al tratamiento. Por último, y con la intención de evaluar el impacto de los marcadores evaluados en la pCR (Pathological Clinical Response), se realizó un análisis PCA (Principal Component Analysis) con las variables correspondientes a la información clínica de las pacientes y los puntajes de las marcaciones de inmunohistoquímica de las cinco poblaciones inmunes evaluadas. En este análisis las variables fueron procesadas de forma directa y posteriormente optimizadas filtrando las variables de mayor peso. Sin embargo, ninguno de estos análisis nos permitió establecer correlaciones entre los marcadores evaluados y el pronóstico clínico de las pacientes. Sin embargo, realizando un análisis con dos variables seleccionadas: i) infiltrado de células CD45+ el cual aumentó significativamente pos-NAC; ii) infiltración de células CD68+ que mostró una tendencia al aumento, y las variables de tamaño y grado de reducción tumoral, fue posible evidenciar una segregación diferencial de las muestras pre y pos-NAC. (Texto tomado de la fuente)Breast cancer is the third deadliest cancer in Colombia, having the highest incidence and prevalence in women. Tumor surveillance in breast cancer patients by immune system cells -immunosurveillance- it’s a key factor to control tumor growth. A growing body of evidence suggest that a neoadjuvant chemotherapy scheme with Doxorubicin and Cyclophosphamide induces a special type of tumor cell death known as immunogenic cell death, which activates intratumoral immune populations and favours immunosurveillance of this tumor, probably contributing to a better clinical response to antitumor treatment. Studies show that the tumor microenvironment is a determining factor in the prognosis of cancer patients. Although in breast cancer tumors the importance of analyzing the immune infiltrate to evaluate the presence of effector and regulatory populations has been described, the discovery and validation of prognostic biomarkers in response to treatment is still limited. In this work we standardized a sequential immunohistochemistry methodology for the characterization of innate and adaptive immune system populations such as: i) Total CD45+ leukocytes ii) CD68+ macrophages iii). CD20+ B cells iv). CD3+ total T cells and v).CD8+ cytotoxic T cells, in relation to tumor cells evaluated with the Pankeratin marker. Our results showed that this technique represents a cost-effective alternative to map the tumor microenvironment, which allowed us to evaluate the infiltration of these populations before and after chemotherapy, finding a significant increase in the infiltration of CD45 positive cells after neoadjuvant treatment. Additionally, we used the CIBERSORTx tool to measure twenty-two immune subpopulations, with data available in the genome European archive, by analyzing the tumor transcriptome. Significant changes were found in different populations: first, an increase after one cycle of NAC of the relative fractions of: CD8 T cells, quiescent CD4 T cells and regulatory T lymphocytes; decreasing at the end of the treatment. Second, the relative fractions of memory B lymphocytes, M1 macrophages, and follicular T cells decreased after one cycle and at the end of treatment. Finally, activated Dendritic Cells, M2 Macrophages, and Mast Cells increased after one cycle, and also at the end of treatment. On the other hand, we performed a systematic review that allowed us to include 32 articles for a qualitative synthesis of the evidence, and 9 articles, for a quantitative synthesis by meta-analysis, in which we found a significant decrease in the infiltration of TILs, evaluated morphologically on hematoxylin and eosin slides, as well as the reduction FoxP3+ cells, measured by traditional immunohistochemistry, suggesting a decrease in the populations of regulatory T lymphocytes in response to NAC. Total CD3+ T lymphocyte, CD4+ helper T lymphocyte and CD8+ cytotoxic T lymphocyte populations did not change significantly in response to treatment. Finally with the intention of correlate the evaluated markers and pCR (Pathological Clinical Response), a PCA (Principal Component Analysis) analysis was performed with the variables corresponding to the clinical information of the patients and the scores of the immunohistochemical results of the five immune populations evaluated. In the first analysis, the variables were processed directly, and in the second the variables were optimized by filtering the ones with the greatest weight. However, none of these analyzes allowed us to establish correlations between the markers evaluated and the clinical prognosis of the patients. 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J Immunol, 2009. 183(1): p. 155-63.Neoplasias de la MamaAcciones TerapéuticasMicroambiente inmune tumoralCáncer de mamaInmunovigilanciaQuimioterapia neoadyuvanteTumor immune microenvironmentImmunosurveillanceNeoadjuvant chemotherapyBreast CancerLICENSElicense.txtlicense.txttext/plain; charset=utf-85879https://repositorio.unal.edu.co/bitstream/unal/83670/1/license.txteb34b1cf90b7e1103fc9dfd26be24b4aMD51ORIGINAL1098311523.2023.pdf1098311523.2023.pdfTesis de Maestría en Ciencias - Bioquímicaapplication/pdf4441160https://repositorio.unal.edu.co/bitstream/unal/83670/2/1098311523.2023.pdf607361090be86fa401b81d50b5a88503MD52THUMBNAIL1098311523.2023.pdf.jpg1098311523.2023.pdf.jpgGenerated Thumbnailimage/jpeg4166https://repositorio.unal.edu.co/bitstream/unal/83670/3/1098311523.2023.pdf.jpg0efa230a1eb8b7621d007789cf1a2c3fMD53unal/83670oai:repositorio.unal.edu.co:unal/836702024-07-31 23:12:50.275Repositorio Institucional Universidad Nacional de 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