Avaliação do perfil de agregado plaquetário circulante e da expressão de OX40, CD40L e 4-1BB em pacientes idosos com câncer colorretal
Arquivos
Data
2017-12-20
Autores
Lima, Petrus Moura de Andrade 
Orientadores
Forones, Nora Manoukian
Tipo
Tese de doutorado
Título da Revista
ISSN da Revista
Título de Volume
Resumo
A cada ano, mais de 1,2 milhões de pessoas são diagnosticadas com câncer colorretal (CCR) e cerca de 600.000 pessoas morrem por causa dessa doença. A incidência do câncer de cólon aumenta com a idade. O prognóstico dos pacientes com CCR tem melhorado nas últimas décadas, contudo, persiste uma sobrevida global menor nos idosos. O ambiente tumoral é composto por células do sistema imune, que refletem a tentativa desse sistema em promover uma resposta antitumoral. Complexas interações entre células e mediadores imunes no microambiente tecidual regulam o crescimento de tumores, progressão, metástase e angiogênese. O entendimento das alterações da imunidade na população idosa com CCR permitirá o surgimento de novos tratamentos com maiores taxas de resposta. O presente estudo teve por objetivo avaliar o perfil de agregado plaquetário circulante e da expressão de OX40, CD40L e 4-1BB em idosos com câncer colorretal. Foi realizado um estudo de corte transversal e translacional com grupo de comparação interna, envolvendo 41 idosos portadores de CCR e 75 idosos saudáveis. Foi realizada a análise dos valores percentuais de leucócitos, de agregado de plaquetas ativadas aos linfócitos, monócitos e neutrófilos no sangue periférico, e também a análise dos percentuais de expressão de OX40, p-selectina (CD62P) e CD40L em células T, B, neutrófilo e plaquetas por citometria de fluxo. Dosagem no plasma de s4-1BB e sCD40L por enzyme linked immunosorbentassay (ELISA). Testes de Mann-Whitney e Kruskal-Wallis foram usados para análise de medianas entre dois e três grupos, respectivamente. As variáveis de distribuição normal foram apresentadas em média e desvio padrão. Foi utilizado o teste t e ANOVA para a comparação das médias entre dois e três grupos, respectivamente. Foram considerados significantes valores de p<0.05. Toda a análise estatística foi realizada através do GraphPadPrism v6.0 Verificou-se níveis percentuais diminuídos de plaquetas/OX40+ nos pacientes com CCR (p<0,0001). Os níveis percentuais de linfócitos B/OX40+ estiveram aumentados nos pacientes metastáticos (p=0,01). Na análise do agregado de plaquetas em leucócitos no sangue periférico, verificou-se que os pacientes apresentaram níveis percentuais reduzidos de AGP-neutrófilos (p=0,004). Os pacientes apresentaram um elevado percentual de plaquetas expressando CD62P quando comparado aos controles (p=0,003). Observou-se nos pacientes valores percentuais reduzidos de expressão de CD40L em plaquetas (p<0,0001) e agregado de plaquetas a leucócitos. Os pacientes apresentaram níveis séricos reduzidos de sCD40L quando comparado aos controles (p=0,002). Os idosos com CCR possuem uma imunossupressão que favorece a progressão da doença. Esse conhecimento reveste-se de importância pela possibilidade do surgimento de novas terapias que possam ativar os mecanismos da resposta imune frente aos antígenos tumorais no CCR.
Each year, more than 1.2 million people are diagnosed with colorectal cancer (CRC) and about 600,000 people die from it. The incidence of colon cancer increases with age. The prognosis of patients with CRC has improved in the last decades.However, a lower overall survival persists in the elderly. The tumor environment is composed of cells of the immune system, which reflect the attempt of this system to promote an antitumor response. Complex interactions between immune cells and mediators in the tissue microenvironment regulate tumor growth, progression, metastasis and angiogenesis. The understanding of immunity changes in the elderly population with CRC will allow the emergence of new treatments with higher response rates. Evaluate the profile of circulating platelet aggregation and expression of OX40, CD40L and 4-1BB in the elderly with colorectal cancer. A cross-sectional and translational study was conducted with an internal comparison group, involving 41 elderly patients with CRC and 75 healthy elderly. The percentage values of leukocytes, aggregation of activated platelets, lymphocytes, monocytes and neutrophils in the peripheral blood were analyzed, as well as analysis of percentages of OX40, P-selectin (CD62P) and CD40L expression in T, B, neutrophil and platelets by flow cytometry. Plasma dosing of s4-1BB and sCD40L by enzyme linked immunosorbent assay (ELISA). Mann-Whitney and Kruskal Wallis tests were used for analysis of medians between two and three groups, respectively. The variables of normal distribution were presented in mean and standard deviation. The t-test and ANOVA were used to compare the means between two and three groups, respectively. Significant values of p <0.05 were considered. All statistical analysis was performed using GraphPadPrism v6.0. Decreased percentage platelet/OX40+levels were found in patients with CRC (p <0.0001). Percentage levels of B/OX40+lymphocytes were increased in metastatic patients (p = 0.01). In the analysis of the platelet aggregate in leukocytes in peripheral blood, patients were found to have reduced percentage levels of platelet aggregates to neutrophils (p = 0.004). Patients presented a high percentage of platelets expressing CD62P when compared to controls (p = 0.003). Reduced percentages of CD40L expression in platelets (p<0.0001) and platelet aggregates to leukocytes were observed in the patients. Patients presented reduced serum levels of sCD40L when compared to controls (p=0.002). Elderly patients with CRC have an immunosuppression that favors the progression of the disease. This knowledge is of importance for the possibility of the emergence of new therapies that can activate the mechanisms of the immune response to the tumor antigens in the CRC.
Each year, more than 1.2 million people are diagnosed with colorectal cancer (CRC) and about 600,000 people die from it. The incidence of colon cancer increases with age. The prognosis of patients with CRC has improved in the last decades.However, a lower overall survival persists in the elderly. The tumor environment is composed of cells of the immune system, which reflect the attempt of this system to promote an antitumor response. Complex interactions between immune cells and mediators in the tissue microenvironment regulate tumor growth, progression, metastasis and angiogenesis. The understanding of immunity changes in the elderly population with CRC will allow the emergence of new treatments with higher response rates. Evaluate the profile of circulating platelet aggregation and expression of OX40, CD40L and 4-1BB in the elderly with colorectal cancer. A cross-sectional and translational study was conducted with an internal comparison group, involving 41 elderly patients with CRC and 75 healthy elderly. The percentage values of leukocytes, aggregation of activated platelets, lymphocytes, monocytes and neutrophils in the peripheral blood were analyzed, as well as analysis of percentages of OX40, P-selectin (CD62P) and CD40L expression in T, B, neutrophil and platelets by flow cytometry. Plasma dosing of s4-1BB and sCD40L by enzyme linked immunosorbent assay (ELISA). Mann-Whitney and Kruskal Wallis tests were used for analysis of medians between two and three groups, respectively. The variables of normal distribution were presented in mean and standard deviation. The t-test and ANOVA were used to compare the means between two and three groups, respectively. Significant values of p <0.05 were considered. All statistical analysis was performed using GraphPadPrism v6.0. Decreased percentage platelet/OX40+levels were found in patients with CRC (p <0.0001). Percentage levels of B/OX40+lymphocytes were increased in metastatic patients (p = 0.01). In the analysis of the platelet aggregate in leukocytes in peripheral blood, patients were found to have reduced percentage levels of platelet aggregates to neutrophils (p = 0.004). Patients presented a high percentage of platelets expressing CD62P when compared to controls (p = 0.003). Reduced percentages of CD40L expression in platelets (p<0.0001) and platelet aggregates to leukocytes were observed in the patients. Patients presented reduced serum levels of sCD40L when compared to controls (p=0.002). Elderly patients with CRC have an immunosuppression that favors the progression of the disease. This knowledge is of importance for the possibility of the emergence of new therapies that can activate the mechanisms of the immune response to the tumor antigens in the CRC.
Descrição
Citação
LIMA, Petrus Moura de Andrade. Avaliação do perfil de agregado plaquetário circulante e da expressão de OX40, CD40L e 4-1BB em pacientes idosos com câncer colorretal. 2017. São Paulo, [79] p. Tese (Doutorado em Medicina translacional) - Escola Paulista de Medicina (EPM), Universidade Federal de São Paulo (UNIFESP), São Paulo, 2017.