Avaliação da expressão da proteína da morte celular programada 1 (PD-1) em crianças e adolescentes com Linfoma de Hodgkin clássico
Data
2022-11-07
Autores
Barlera, Tais Tavares 
Orientadores
Caran, Eliana Maria Monteiro
Tipo
Dissertação de mestrado
Título da Revista
ISSN da Revista
Título de Volume
Resumo
Introdução: o linfoma de Hodgkin é uma neoplasia hematológica de células B que afeta principalmente adolescentes e adultos jovens. Estudos recentes descreveram no microambiente tumoral a interação de ligantes presentes nas células de Reed Sternberg, o ligante de morte programada 1 (PD-L1) com receptores expressos por células T. Essa ligação PD-L1 com a proteína de morte programada 1 (PD-1), reduz a eficácia das células T, tornando o sistema imunológico inoperante contra as células tumorais. Terapias para inibir o checkpoint imunológico PD-1/PD-L1, têm sido desenvolvidas com o objetivo de manter o sistema imune celular ativo contra células tumorais, levando a regressão da neoplasia. Atualmente, o Pembrolizumab anticorpo anti-PD-1, foi aprovado pelo FDA como boa opção no tratamento de linfoma de Hodgkin clássico (LHC). Objetivos: avaliar a expressão da proteína da morte celular programada 1 (PD-1) em crianças e adolescentes com LHC. Correlacionar a presença do marcador PD-1 a parâmetros clínicos. Comparar os dados clínicos da casuística apresentada com os dados da literatura. Métodos: estudo retrospectivo em pacientes com LHC, idade até 21 anos, admitidos entre janeiro de 2009 a fevereiro de 2019. Foi realizada análise quantitativa da imunoexpressão do marcador PD-1, utilizando um sistema digital de imagem que consiste em um microcomputador acoplado a uma câmera com placa digitalizadora, trabalhando em ambiente Windows, com o software Image J (NIH USA). A captura das imagens se baseou no princípio do hot spot, iniciando na área mais positiva das amostras com captura dos demais campos de maneira consecutiva. Após a captura das imagens foi desenvolvida uma macro no Programa Image J, onde essas imagens foram trabalhadas, realizando um “Treshold” e “Binarização” das mesmas para quantificação por meio do software. Foram obtidas a média e mediana da expressão do marcador para cada um dos casos, classificando as amostras como de baixa ou alta expressão do PD-1. O estudo foi aprovado pelo comitê de ética da UNIFESP. Resultados: foi observada tendência de menor expressão do PD-1 no sexo feminino (p = 0,095) e alta expressão do PD-1 em pacientes com déficit nutricional (p = 0,073). Conclusão: todas as amostras tumorais apresentaram expressão do PD-1. Não houve correlação da expressão do PD-1 com nenhum parâmetro clínico, Sobrevida Global ou Livre de Eventos. A população estudada representa de maneira geral o universo dos pacientes com LHC exceto pela porcentagem de pacientes com VHS aumentado e presença de sintomas B.
Background: Hodgkin's lymphoma is a hematologic B-cell neoplasm that mainly affects adolescents and young adults. Recent studies have described in the tumor microenvironment the interaction of ligands present in Reed Sternberg cells, the programmed death ligand 1 (PD-L1) with receptors expressed by T cells. This PD-L1 binding with the protein program death 1 (PD -1), reduces the effectiveness of T cells, rendering the immune system inoperative against tumor cells. Therapies to inhibit the PD-1/PD-L1 immune checkpoint have been developed with the aim of keeping the cellular immune system active against tumor cells, leading to tumor regression. Currently, the Pembrolizumab anti-PD-1 antibody has been approved by the FDA as a good option in the treatment of Classical Hodgkin's Lymphoma. Objective: to evaluate the expression of programmed cell death protein 1 (PD-1) in children and adolescents with LHC. Correlate the presence of the PD-1 marker to clinical parameters. Compare the clinical data of the presented series with data from the literature. Methods: retrospective study in patients with LH classic aged up to 21 years, admitted between January 2009 and February 2019. A quantitative analysis of the immunoexpression of the PD-1 marker was performed, using a digital imaging system that consists of a microcomputer coupled to a camera with a digitizing board, working in a Windows environment, with the Image J software (NIH USA). The capture of the images was based on the principle of the hot spot, starting in the most positive area of the samples, capturing the other fields consecutively. After capturing the images, a macro was made in the Image J Program, where these images were processed, performing a “Treshold” and “Binarization” of the same for quantification through the software. The study was approved by the UNIFESP ethics committee. Results: Only the presence of Symptoms B was marginally significant (p=0.072) with a greater tendency to die from the disease. We observed a trend of lower expression of PD-1 in females (p = 0.095) and 7 times more likely to have nutritional deficit (p = 0.073) associated with those with high expression of PD-1. Conclusion: all tumor samples showed PD-1 expression. There was no correlation of PD-1 expression with any clinical parameter, Overall Survival or Event-Free. The population studied generally represents the universe of patients with classic Hodgkin's lymphoma, except for the percentage of patients with increased VHS and presence of B symptoms.
Background: Hodgkin's lymphoma is a hematologic B-cell neoplasm that mainly affects adolescents and young adults. Recent studies have described in the tumor microenvironment the interaction of ligands present in Reed Sternberg cells, the programmed death ligand 1 (PD-L1) with receptors expressed by T cells. This PD-L1 binding with the protein program death 1 (PD -1), reduces the effectiveness of T cells, rendering the immune system inoperative against tumor cells. Therapies to inhibit the PD-1/PD-L1 immune checkpoint have been developed with the aim of keeping the cellular immune system active against tumor cells, leading to tumor regression. Currently, the Pembrolizumab anti-PD-1 antibody has been approved by the FDA as a good option in the treatment of Classical Hodgkin's Lymphoma. Objective: to evaluate the expression of programmed cell death protein 1 (PD-1) in children and adolescents with LHC. Correlate the presence of the PD-1 marker to clinical parameters. Compare the clinical data of the presented series with data from the literature. Methods: retrospective study in patients with LH classic aged up to 21 years, admitted between January 2009 and February 2019. A quantitative analysis of the immunoexpression of the PD-1 marker was performed, using a digital imaging system that consists of a microcomputer coupled to a camera with a digitizing board, working in a Windows environment, with the Image J software (NIH USA). The capture of the images was based on the principle of the hot spot, starting in the most positive area of the samples, capturing the other fields consecutively. After capturing the images, a macro was made in the Image J Program, where these images were processed, performing a “Treshold” and “Binarization” of the same for quantification through the software. The study was approved by the UNIFESP ethics committee. Results: Only the presence of Symptoms B was marginally significant (p=0.072) with a greater tendency to die from the disease. We observed a trend of lower expression of PD-1 in females (p = 0.095) and 7 times more likely to have nutritional deficit (p = 0.073) associated with those with high expression of PD-1. Conclusion: all tumor samples showed PD-1 expression. There was no correlation of PD-1 expression with any clinical parameter, Overall Survival or Event-Free. The population studied generally represents the universe of patients with classic Hodgkin's lymphoma, except for the percentage of patients with increased VHS and presence of B symptoms.