Análise da expressão da proteína de checkpoint imunológico CTLA-4 em biópsias de pacientes com câncer de mama e seu impacto na produção sistêmica de mediadores da resposta imune
Autor(a) principal: | |
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Data de Publicação: | 2021 |
Tipo de documento: | Dissertação |
Idioma: | por |
Título da fonte: | Biblioteca Digital de Teses e Dissertações do UNIOESTE |
Texto Completo: | http://tede.unioeste.br/handle/tede/5422 |
Resumo: | Purpose: Breast cancer is the leading cause of women’s death among all cancers. It is a heterogeneous disease consisting of subgroups with different molecular features and clinical outcomes. Cancer cells can evade antitumor T- cell responses by expressing some immune inhibitory molecules as the programmed cell death protein 1 (PD-1) and/or the cytotoxic T-lymphocyte associated protein 4 (CTLA-4), known as immune checkpoints, which have the function of reducing or limiting the cellular immune responses in a physiological scenario. Recent evidences have pointed out that the expression of the CTLA-4 in tumors is a poor prognosis factor, but the systemic impact of its expression in tumor or infiltrating leukocytes is not clear for breast cancer. In this context, it is important to investigate CTLA-4 expression in BC microenvironment and its potential role in systemic inflammation modulation. Based on this, we analyzed CTLA-4 expression by immunofluorescence, and according to its expression in tumor or TILs, evaluated the circulating levels of interleukins and oxidative stress mediators known as players of the inflammatory response. This study was approved by the Ethics Committee on Research of State University of Western Paraná under the number CAAE 35524814.4.0000.0107. Methods: Paraffin- embedded breast tumors and whole blood samples were collected from 117 women diagnosed with breast cancer. Clinicopathological data were obtained through medical records. In blood samples, oxidative stress parameters were evaluated by measuring its plasmatic lipoperoxidation by high-sensitivity chemiluminescence and estimating nitric oxide metabolites (NO) by the cadmium-copper system coupled to Griess reaction. Interleukins 12 (IL-12) and 4 (IL-4) were measured in plasma samples by ELISA kits. CTLA-4 expression was determined by immunofluorescence and evaluated by its labeling in tumor- infiltrating leukocytes (TILs) or breast tumors. Statistical analyses were performed using the GraphPad Prism 7.0 software package (GraphPad Software, San Diego, CA, USA). Also, SPSS 22.0 software (IBM, USA) was used to obtain the clinicopathological data frequencies and Spearman’s correlations. Results: CTLA-4 expression in TILs significantly correlated to triple negative breast tumors, Patients carrying CTLA-4 positive tumors exhibited lower plasmatic NO levels, while those with CTLA-4 expression only in TILs exhibited reduced levels of IL-12 in plasma. No variations were observed in IL-4 or lipid peroxidation profiles in any CTLA4 status. Conclusion: CTLA-4 expression in BC is a putative marker of clinical significance as well as a rationale therapeutic target in the emerging field of immunotherapy. Moreover, our findings suggest that CTLA-4 expression in both tumor and TILs can affect the systemic inflammatory status of breast cancer patients, affecting directly the levels of antitumor molecules as IL12 and NO, and correlating to most aggressive disease. |
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Panis, Carolinahttp://lattes.cnpq.br/6647155856678648Panis, Carolina Panishttp://lattes.cnpq.br/6647155856678648Benvegnú, Dalila Moterhttp://lattes.cnpq.br/6134516963963514Victorino, Vanessa Jacobhttp://lattes.cnpq.br/9010315065355652http://lattes.cnpq.br/9578228127153938Kern, Rodrigo2021-06-15T11:48:51Z2021-03-01KERN, Rodrigo. Análise da expressão da proteína de checkpoint imunológico CTLA-4 em biópsias de pacientes com câncer de mama e seu impacto na produção sistêmica de mediadores da resposta imune. 2021. 65 f. Dissertação (Mestrado em Ciências Aplicadas à Saúde) - Universidade Estadual do Oeste do Paraná, Francisco Beltrão, 2021.http://tede.unioeste.br/handle/tede/5422Purpose: Breast cancer is the leading cause of women’s death among all cancers. It is a heterogeneous disease consisting of subgroups with different molecular features and clinical outcomes. Cancer cells can evade antitumor T- cell responses by expressing some immune inhibitory molecules as the programmed cell death protein 1 (PD-1) and/or the cytotoxic T-lymphocyte associated protein 4 (CTLA-4), known as immune checkpoints, which have the function of reducing or limiting the cellular immune responses in a physiological scenario. Recent evidences have pointed out that the expression of the CTLA-4 in tumors is a poor prognosis factor, but the systemic impact of its expression in tumor or infiltrating leukocytes is not clear for breast cancer. In this context, it is important to investigate CTLA-4 expression in BC microenvironment and its potential role in systemic inflammation modulation. Based on this, we analyzed CTLA-4 expression by immunofluorescence, and according to its expression in tumor or TILs, evaluated the circulating levels of interleukins and oxidative stress mediators known as players of the inflammatory response. This study was approved by the Ethics Committee on Research of State University of Western Paraná under the number CAAE 35524814.4.0000.0107. Methods: Paraffin- embedded breast tumors and whole blood samples were collected from 117 women diagnosed with breast cancer. Clinicopathological data were obtained through medical records. In blood samples, oxidative stress parameters were evaluated by measuring its plasmatic lipoperoxidation by high-sensitivity chemiluminescence and estimating nitric oxide metabolites (NO) by the cadmium-copper system coupled to Griess reaction. Interleukins 12 (IL-12) and 4 (IL-4) were measured in plasma samples by ELISA kits. CTLA-4 expression was determined by immunofluorescence and evaluated by its labeling in tumor- infiltrating leukocytes (TILs) or breast tumors. Statistical analyses were performed using the GraphPad Prism 7.0 software package (GraphPad Software, San Diego, CA, USA). Also, SPSS 22.0 software (IBM, USA) was used to obtain the clinicopathological data frequencies and Spearman’s correlations. Results: CTLA-4 expression in TILs significantly correlated to triple negative breast tumors, Patients carrying CTLA-4 positive tumors exhibited lower plasmatic NO levels, while those with CTLA-4 expression only in TILs exhibited reduced levels of IL-12 in plasma. No variations were observed in IL-4 or lipid peroxidation profiles in any CTLA4 status. Conclusion: CTLA-4 expression in BC is a putative marker of clinical significance as well as a rationale therapeutic target in the emerging field of immunotherapy. Moreover, our findings suggest that CTLA-4 expression in both tumor and TILs can affect the systemic inflammatory status of breast cancer patients, affecting directly the levels of antitumor molecules as IL12 and NO, and correlating to most aggressive disease.O câncer de mama (CM), além de apresentar alta incidência populacional, é caracterizado por heterogêneos subtipos moleculares, cada qual com uma biologia tumoral própria. Isso resulta em carcinomas distintos quanto à imunogenicidade e à capacidade de evasão tumoral ao sistema imune. Assim, diversos estudos investigam o significado clínico dos receptores proteicos PD-1 e CTLA-4 (também conhecidos como checkpoints imunológicos), cuja função fisiológica é a modulação negativa da resposta imune celular. Entretanto, o papel do CTLA-4 na biologia tumoral do CM ainda não é completamente compreendido. Portanto, este trabalho tem por objetivo estudar a expressão tecidual de CTLA-4 em amostras de pacientes portadoras de CM, seu impacto na produção de mediadores sistêmicos da resposta imune e sua correlação clínico-patológica. Para isso, pacientes atendidas no Hospital do Câncer de Francisco Beltrão/PR – Brasil no período de 2016 a 2019 foram convidadas a participar do estudo, aprovado pelo Comitê de Ética em Pesquisa Institucional sob o número CAAE N° 35524814.4.0000.0107. Foram incluídas 117 pacientes com diagnóstico anatomopatológico de Carcinoma Ductal Invasivo (CDI). Amostras de sangue periférico heparinizado foram coletadas para avaliação do perfil de mediadores imunológicos circulantes (IL-4 e IL-12 por ELISA; níveis de lipoperóxidos por quimioluminescência; e estimativa de óxido nítrico (NO) pela medida de nitrito via método cádmio-cobre). Lâminas de tecido da ressecção cirúrgica da biópsia foram obtidas para análise da expressão de CTLA-4 por imunofluorescência. Dados clínico-patológicos foram obtidos através de consulta aos prontuários médicos. Foi realizada a análise dos dados no software GraphPad Prism 7.0 (USA) e SPSS 25.0.0 (IBM, USA). Os resultados apresentaram expressão de CTLA-4 significativamente correlacionada ao subtipo molecular triplo negativo. Além disso, pacientes com expressão positiva de CTLA-4 em células tumorais apresentaram níveis reduzidos de NO. Pacientes que apresentaram expressão de CTLA-4 apenas em linfócitos infiltrantes de tumor (LIT) revelaram reduzidos níveis de IL-12 no plasma. Não foram identificadas correlações referentes à análise de IL-4 e peroxidação lipídica. Portanto, os achados do presente trabalho sugerem que a expressão de CTLA4 em microambiente tumoral é capaz de interferir na geração de inflamação sistêmica no câncer de mama, afetando diretamente os níveis de IL-12 e NO, e correlacionando-se com um perfil mais agressivo de doença.Submitted by Almir Squinsani (almir.squinsani@unioeste.br) on 2021-06-15T11:48:51Z No. of bitstreams: 2 Rodrigo_Kern_2021.pdf: 9078432 bytes, checksum: 6fa62aa3e267b442544901dbf43f63ba (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5)Made available in DSpace on 2021-06-15T11:48:51Z (GMT). No. of bitstreams: 2 Rodrigo_Kern_2021.pdf: 9078432 bytes, checksum: 6fa62aa3e267b442544901dbf43f63ba (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) Previous issue date: 2021-03-01application/pdfpor-5356284425524309716500Universidade Estadual do Oeste do ParanáFrancisco BeltrãoPrograma de Pós-Graduação em Ciências Aplicadas à SaúdeUNIOESTEBrasilCentro de Ciências da Saúdehttp://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessCâncer de mamaCheckpoint imunológico CTLA-4Linfócitos infiltrantes de tumorImunidade tumoralEstresse oxidativoLipoperoxidaçãoÓxido nítricoInflamaçãoIL-4IL-12Breast cancerCTLA-4 antigen/antagonists & inhibitorsLymphocytesTumor- Infiltrating/immunologyOxidative stressLipoperoxidationNitric oxideInflammationIL-4IL-12CIÊNCIAS DA SAÚDEAnálise da expressão da proteína de checkpoint imunológico CTLA-4 em biópsias de pacientes com câncer de mama e seu impacto na produção sistêmica de mediadores da resposta imuneEvaluation of CTLA-4 expression and its influence in systemic inflammatory response of breast cancer patientsinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/masterThesis6290525253230630664600600292441653440865123reponame:Biblioteca Digital de Teses e Dissertações do UNIOESTEinstname:Universidade Estadual do Oeste do Paraná (UNIOESTE)instacron:UNIOESTEORIGINALRodrigo_Kern_2021-compactado.pdfRodrigo_Kern_2021-compactado.pdfapplication/pdf2611472http://tede.unioeste.br:8080/tede/bitstream/tede/5422/6/Rodrigo_Kern_2021-compactado.pdfa3f0c095371a108c8b53885053a051a4MD56CC-LICENSElicense_urllicense_urltext/plain; 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dc.title.por.fl_str_mv |
Análise da expressão da proteína de checkpoint imunológico CTLA-4 em biópsias de pacientes com câncer de mama e seu impacto na produção sistêmica de mediadores da resposta imune |
dc.title.alternative.eng.fl_str_mv |
Evaluation of CTLA-4 expression and its influence in systemic inflammatory response of breast cancer patients |
title |
Análise da expressão da proteína de checkpoint imunológico CTLA-4 em biópsias de pacientes com câncer de mama e seu impacto na produção sistêmica de mediadores da resposta imune |
spellingShingle |
Análise da expressão da proteína de checkpoint imunológico CTLA-4 em biópsias de pacientes com câncer de mama e seu impacto na produção sistêmica de mediadores da resposta imune Kern, Rodrigo Câncer de mama Checkpoint imunológico CTLA-4 Linfócitos infiltrantes de tumor Imunidade tumoral Estresse oxidativo Lipoperoxidação Óxido nítrico Inflamação IL-4 IL-12 Breast cancer CTLA-4 antigen/antagonists & inhibitors Lymphocytes Tumor- Infiltrating/immunology Oxidative stress Lipoperoxidation Nitric oxide Inflammation IL-4 IL-12 CIÊNCIAS DA SAÚDE |
title_short |
Análise da expressão da proteína de checkpoint imunológico CTLA-4 em biópsias de pacientes com câncer de mama e seu impacto na produção sistêmica de mediadores da resposta imune |
title_full |
Análise da expressão da proteína de checkpoint imunológico CTLA-4 em biópsias de pacientes com câncer de mama e seu impacto na produção sistêmica de mediadores da resposta imune |
title_fullStr |
Análise da expressão da proteína de checkpoint imunológico CTLA-4 em biópsias de pacientes com câncer de mama e seu impacto na produção sistêmica de mediadores da resposta imune |
title_full_unstemmed |
Análise da expressão da proteína de checkpoint imunológico CTLA-4 em biópsias de pacientes com câncer de mama e seu impacto na produção sistêmica de mediadores da resposta imune |
title_sort |
Análise da expressão da proteína de checkpoint imunológico CTLA-4 em biópsias de pacientes com câncer de mama e seu impacto na produção sistêmica de mediadores da resposta imune |
author |
Kern, Rodrigo |
author_facet |
Kern, Rodrigo |
author_role |
author |
dc.contributor.advisor1.fl_str_mv |
Panis, Carolina |
dc.contributor.advisor1Lattes.fl_str_mv |
http://lattes.cnpq.br/6647155856678648 |
dc.contributor.referee1.fl_str_mv |
Panis, Carolina Panis |
dc.contributor.referee1Lattes.fl_str_mv |
http://lattes.cnpq.br/6647155856678648 |
dc.contributor.referee2.fl_str_mv |
Benvegnú, Dalila Moter |
dc.contributor.referee2Lattes.fl_str_mv |
http://lattes.cnpq.br/6134516963963514 |
dc.contributor.referee3.fl_str_mv |
Victorino, Vanessa Jacob |
dc.contributor.referee3Lattes.fl_str_mv |
http://lattes.cnpq.br/9010315065355652 |
dc.contributor.authorLattes.fl_str_mv |
http://lattes.cnpq.br/9578228127153938 |
dc.contributor.author.fl_str_mv |
Kern, Rodrigo |
contributor_str_mv |
Panis, Carolina Panis, Carolina Panis Benvegnú, Dalila Moter Victorino, Vanessa Jacob |
dc.subject.por.fl_str_mv |
Câncer de mama Checkpoint imunológico CTLA-4 Linfócitos infiltrantes de tumor Imunidade tumoral Estresse oxidativo Lipoperoxidação Óxido nítrico Inflamação IL-4 IL-12 |
topic |
Câncer de mama Checkpoint imunológico CTLA-4 Linfócitos infiltrantes de tumor Imunidade tumoral Estresse oxidativo Lipoperoxidação Óxido nítrico Inflamação IL-4 IL-12 Breast cancer CTLA-4 antigen/antagonists & inhibitors Lymphocytes Tumor- Infiltrating/immunology Oxidative stress Lipoperoxidation Nitric oxide Inflammation IL-4 IL-12 CIÊNCIAS DA SAÚDE |
dc.subject.eng.fl_str_mv |
Breast cancer CTLA-4 antigen/antagonists & inhibitors Lymphocytes Tumor- Infiltrating/immunology Oxidative stress Lipoperoxidation Nitric oxide Inflammation IL-4 IL-12 |
dc.subject.cnpq.fl_str_mv |
CIÊNCIAS DA SAÚDE |
description |
Purpose: Breast cancer is the leading cause of women’s death among all cancers. It is a heterogeneous disease consisting of subgroups with different molecular features and clinical outcomes. Cancer cells can evade antitumor T- cell responses by expressing some immune inhibitory molecules as the programmed cell death protein 1 (PD-1) and/or the cytotoxic T-lymphocyte associated protein 4 (CTLA-4), known as immune checkpoints, which have the function of reducing or limiting the cellular immune responses in a physiological scenario. Recent evidences have pointed out that the expression of the CTLA-4 in tumors is a poor prognosis factor, but the systemic impact of its expression in tumor or infiltrating leukocytes is not clear for breast cancer. In this context, it is important to investigate CTLA-4 expression in BC microenvironment and its potential role in systemic inflammation modulation. Based on this, we analyzed CTLA-4 expression by immunofluorescence, and according to its expression in tumor or TILs, evaluated the circulating levels of interleukins and oxidative stress mediators known as players of the inflammatory response. This study was approved by the Ethics Committee on Research of State University of Western Paraná under the number CAAE 35524814.4.0000.0107. Methods: Paraffin- embedded breast tumors and whole blood samples were collected from 117 women diagnosed with breast cancer. Clinicopathological data were obtained through medical records. In blood samples, oxidative stress parameters were evaluated by measuring its plasmatic lipoperoxidation by high-sensitivity chemiluminescence and estimating nitric oxide metabolites (NO) by the cadmium-copper system coupled to Griess reaction. Interleukins 12 (IL-12) and 4 (IL-4) were measured in plasma samples by ELISA kits. CTLA-4 expression was determined by immunofluorescence and evaluated by its labeling in tumor- infiltrating leukocytes (TILs) or breast tumors. Statistical analyses were performed using the GraphPad Prism 7.0 software package (GraphPad Software, San Diego, CA, USA). Also, SPSS 22.0 software (IBM, USA) was used to obtain the clinicopathological data frequencies and Spearman’s correlations. Results: CTLA-4 expression in TILs significantly correlated to triple negative breast tumors, Patients carrying CTLA-4 positive tumors exhibited lower plasmatic NO levels, while those with CTLA-4 expression only in TILs exhibited reduced levels of IL-12 in plasma. No variations were observed in IL-4 or lipid peroxidation profiles in any CTLA4 status. Conclusion: CTLA-4 expression in BC is a putative marker of clinical significance as well as a rationale therapeutic target in the emerging field of immunotherapy. Moreover, our findings suggest that CTLA-4 expression in both tumor and TILs can affect the systemic inflammatory status of breast cancer patients, affecting directly the levels of antitumor molecules as IL12 and NO, and correlating to most aggressive disease. |
publishDate |
2021 |
dc.date.accessioned.fl_str_mv |
2021-06-15T11:48:51Z |
dc.date.issued.fl_str_mv |
2021-03-01 |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/masterThesis |
format |
masterThesis |
status_str |
publishedVersion |
dc.identifier.citation.fl_str_mv |
KERN, Rodrigo. Análise da expressão da proteína de checkpoint imunológico CTLA-4 em biópsias de pacientes com câncer de mama e seu impacto na produção sistêmica de mediadores da resposta imune. 2021. 65 f. Dissertação (Mestrado em Ciências Aplicadas à Saúde) - Universidade Estadual do Oeste do Paraná, Francisco Beltrão, 2021. |
dc.identifier.uri.fl_str_mv |
http://tede.unioeste.br/handle/tede/5422 |
identifier_str_mv |
KERN, Rodrigo. Análise da expressão da proteína de checkpoint imunológico CTLA-4 em biópsias de pacientes com câncer de mama e seu impacto na produção sistêmica de mediadores da resposta imune. 2021. 65 f. Dissertação (Mestrado em Ciências Aplicadas à Saúde) - Universidade Estadual do Oeste do Paraná, Francisco Beltrão, 2021. |
url |
http://tede.unioeste.br/handle/tede/5422 |
dc.language.iso.fl_str_mv |
por |
language |
por |
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