Clinical implications of T-Cells CX3CR1+, Toll-like Receptor 4 signaling pathway, and immune checkpoints in Non-Muscle Invasive Bladder Cancer
Autor(a) principal: | |
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Data de Publicação: | 2023 |
Outros Autores: | , , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Brazilian Journal of Health Review |
Texto Completo: | https://ojs.brazilianjournals.com.br/ojs/index.php/BJHR/article/view/59226 |
Resumo: | Background: This study characterized and compared the molecular profiles of CX3C chemokine receptor 1 (CX3CR1, a marker of T-cell differentiation), Toll-like receptor 4 (TLR4)-mediated interferon signaling pathway, and immune checkpoints in the different histological stages of non-muscle invasive bladder cancer (NMIBC), aiming the investigation of these biomarkers as a criterion of clinical response to immunotherapy. Methods: Seventy-five formalin-fixed paraffin-embedded samples of bladder were obtained from 34 to 96-year-old patients (mean 65 years) with NMIBC diagnosis in University of Campinas (UNICAMP) and Paulinia Municipal Hospital/ Brazil. Subsequently, the samples were divided into 3 groups (n= 25 samples per group): pTis group, high-grade pTa group, and pT1 group; and submitted to immunohistochemistry analysis: TLR4-mediated IFN-γ production signaling pathway (TRIF, TBK1, IRF-3, IFN-γ), CX3CR1+CD8+ T-cells, immune checkpoints (PD-1/PD-L1 and CTLA-4), and regulatory T (Treg) cells (FOXP3). The retrospective anonymous study was approved by the local ethics committee (Clinical Trial: RBR-6swqd2). Results: pTis group showed the lowest activation of TLR4-mediated IFN-γ signaling pathway when compared (p<0.01) to high-grade pTa and pT1 groups. Both the immunoreaction intensity and positive cells percentage were lower (p<0.01) for TLR4, TRIF, IRF-3, and IFN-γ in the pTis group with respect to other groups. No statistical difference was found between high-grade pTa and pT1 groups for these biomarkers. Likewise, CX3CR1 immunoreactivities were remarkably lower (p<0.01) in the pTis group in comparison with high-grade pTa and pT1 groups, which did not show statistical differences between them. Furthermore, immune checkpoints (PD-1/PD-L1 and CTLA4) and FOXP3+ Treg cells immunoreactivities were significantly higher (p<0.01) in the high-grade pTa and pT1 compared to the pTis group. Conclusions: Our data demonstrated that pTis stage was characterized by an immunosuppressive microenvironment in comparison with pTa and pT1 stages, showing decreased TLR4-mediated interferon signaling pathway and low activation of CX3CR1+CD8+ T-cells; which implies in low sensitivity to immunotherapy. The larger number of FOXP3+ Treg cells in pTa and pT1 was correlated with intensified immune checkpoints immunoreactivities, indicating higher sensitivity to immunotherapy. Finally, these biomarkers may be useful in the clinical management of patients with NMIBC. |
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Brazilian Journal of Health Review |
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Clinical implications of T-Cells CX3CR1+, Toll-like Receptor 4 signaling pathway, and immune checkpoints in Non-Muscle Invasive Bladder CancerBladder CancerToll-like receptor 4CX3CR1Background: This study characterized and compared the molecular profiles of CX3C chemokine receptor 1 (CX3CR1, a marker of T-cell differentiation), Toll-like receptor 4 (TLR4)-mediated interferon signaling pathway, and immune checkpoints in the different histological stages of non-muscle invasive bladder cancer (NMIBC), aiming the investigation of these biomarkers as a criterion of clinical response to immunotherapy. Methods: Seventy-five formalin-fixed paraffin-embedded samples of bladder were obtained from 34 to 96-year-old patients (mean 65 years) with NMIBC diagnosis in University of Campinas (UNICAMP) and Paulinia Municipal Hospital/ Brazil. Subsequently, the samples were divided into 3 groups (n= 25 samples per group): pTis group, high-grade pTa group, and pT1 group; and submitted to immunohistochemistry analysis: TLR4-mediated IFN-γ production signaling pathway (TRIF, TBK1, IRF-3, IFN-γ), CX3CR1+CD8+ T-cells, immune checkpoints (PD-1/PD-L1 and CTLA-4), and regulatory T (Treg) cells (FOXP3). The retrospective anonymous study was approved by the local ethics committee (Clinical Trial: RBR-6swqd2). Results: pTis group showed the lowest activation of TLR4-mediated IFN-γ signaling pathway when compared (p<0.01) to high-grade pTa and pT1 groups. Both the immunoreaction intensity and positive cells percentage were lower (p<0.01) for TLR4, TRIF, IRF-3, and IFN-γ in the pTis group with respect to other groups. No statistical difference was found between high-grade pTa and pT1 groups for these biomarkers. Likewise, CX3CR1 immunoreactivities were remarkably lower (p<0.01) in the pTis group in comparison with high-grade pTa and pT1 groups, which did not show statistical differences between them. Furthermore, immune checkpoints (PD-1/PD-L1 and CTLA4) and FOXP3+ Treg cells immunoreactivities were significantly higher (p<0.01) in the high-grade pTa and pT1 compared to the pTis group. Conclusions: Our data demonstrated that pTis stage was characterized by an immunosuppressive microenvironment in comparison with pTa and pT1 stages, showing decreased TLR4-mediated interferon signaling pathway and low activation of CX3CR1+CD8+ T-cells; which implies in low sensitivity to immunotherapy. The larger number of FOXP3+ Treg cells in pTa and pT1 was correlated with intensified immune checkpoints immunoreactivities, indicating higher sensitivity to immunotherapy. Finally, these biomarkers may be useful in the clinical management of patients with NMIBC.Brazilian Journals Publicações de Periódicos e Editora Ltda.2023-04-27info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfhttps://ojs.brazilianjournals.com.br/ojs/index.php/BJHR/article/view/5922610.34119/bjhrv6n2-307Brazilian Journal of Health Review; Vol. 6 No. 2 (2023); 8301-8313Brazilian Journal of Health Review; Vol. 6 Núm. 2 (2023); 8301-8313Brazilian Journal of Health Review; v. 6 n. 2 (2023); 8301-83132595-6825reponame:Brazilian Journal of Health Reviewinstname:Federação das Indústrias do Estado do Paraná (FIEP)instacron:BJRHenghttps://ojs.brazilianjournals.com.br/ojs/index.php/BJHR/article/view/59226/42936Alonso, João Carlos Cardosode Souza, Bianca RibeiroCamargo, Gabriela Cardoso de Arrudade Oliveira, GabrielaDurán, Nelsonde Freitas, Leandro Luiz LopesBillis, AthanaseFávaro, Wagner Joséinfo:eu-repo/semantics/openAccess2023-04-27T21:04:07Zoai:ojs2.ojs.brazilianjournals.com.br:article/59226Revistahttp://www.brazilianjournals.com/index.php/BJHR/indexPRIhttps://ojs.brazilianjournals.com.br/ojs/index.php/BJHR/oai|| brazilianjhr@gmail.com2595-68252595-6825opendoar:2023-04-27T21:04:07Brazilian Journal of Health Review - Federação das Indústrias do Estado do Paraná (FIEP)false |
dc.title.none.fl_str_mv |
Clinical implications of T-Cells CX3CR1+, Toll-like Receptor 4 signaling pathway, and immune checkpoints in Non-Muscle Invasive Bladder Cancer |
title |
Clinical implications of T-Cells CX3CR1+, Toll-like Receptor 4 signaling pathway, and immune checkpoints in Non-Muscle Invasive Bladder Cancer |
spellingShingle |
Clinical implications of T-Cells CX3CR1+, Toll-like Receptor 4 signaling pathway, and immune checkpoints in Non-Muscle Invasive Bladder Cancer Alonso, João Carlos Cardoso Bladder Cancer Toll-like receptor 4 CX3CR1 |
title_short |
Clinical implications of T-Cells CX3CR1+, Toll-like Receptor 4 signaling pathway, and immune checkpoints in Non-Muscle Invasive Bladder Cancer |
title_full |
Clinical implications of T-Cells CX3CR1+, Toll-like Receptor 4 signaling pathway, and immune checkpoints in Non-Muscle Invasive Bladder Cancer |
title_fullStr |
Clinical implications of T-Cells CX3CR1+, Toll-like Receptor 4 signaling pathway, and immune checkpoints in Non-Muscle Invasive Bladder Cancer |
title_full_unstemmed |
Clinical implications of T-Cells CX3CR1+, Toll-like Receptor 4 signaling pathway, and immune checkpoints in Non-Muscle Invasive Bladder Cancer |
title_sort |
Clinical implications of T-Cells CX3CR1+, Toll-like Receptor 4 signaling pathway, and immune checkpoints in Non-Muscle Invasive Bladder Cancer |
author |
Alonso, João Carlos Cardoso |
author_facet |
Alonso, João Carlos Cardoso de Souza, Bianca Ribeiro Camargo, Gabriela Cardoso de Arruda de Oliveira, Gabriela Durán, Nelson de Freitas, Leandro Luiz Lopes Billis, Athanase Fávaro, Wagner José |
author_role |
author |
author2 |
de Souza, Bianca Ribeiro Camargo, Gabriela Cardoso de Arruda de Oliveira, Gabriela Durán, Nelson de Freitas, Leandro Luiz Lopes Billis, Athanase Fávaro, Wagner José |
author2_role |
author author author author author author author |
dc.contributor.author.fl_str_mv |
Alonso, João Carlos Cardoso de Souza, Bianca Ribeiro Camargo, Gabriela Cardoso de Arruda de Oliveira, Gabriela Durán, Nelson de Freitas, Leandro Luiz Lopes Billis, Athanase Fávaro, Wagner José |
dc.subject.por.fl_str_mv |
Bladder Cancer Toll-like receptor 4 CX3CR1 |
topic |
Bladder Cancer Toll-like receptor 4 CX3CR1 |
description |
Background: This study characterized and compared the molecular profiles of CX3C chemokine receptor 1 (CX3CR1, a marker of T-cell differentiation), Toll-like receptor 4 (TLR4)-mediated interferon signaling pathway, and immune checkpoints in the different histological stages of non-muscle invasive bladder cancer (NMIBC), aiming the investigation of these biomarkers as a criterion of clinical response to immunotherapy. Methods: Seventy-five formalin-fixed paraffin-embedded samples of bladder were obtained from 34 to 96-year-old patients (mean 65 years) with NMIBC diagnosis in University of Campinas (UNICAMP) and Paulinia Municipal Hospital/ Brazil. Subsequently, the samples were divided into 3 groups (n= 25 samples per group): pTis group, high-grade pTa group, and pT1 group; and submitted to immunohistochemistry analysis: TLR4-mediated IFN-γ production signaling pathway (TRIF, TBK1, IRF-3, IFN-γ), CX3CR1+CD8+ T-cells, immune checkpoints (PD-1/PD-L1 and CTLA-4), and regulatory T (Treg) cells (FOXP3). The retrospective anonymous study was approved by the local ethics committee (Clinical Trial: RBR-6swqd2). Results: pTis group showed the lowest activation of TLR4-mediated IFN-γ signaling pathway when compared (p<0.01) to high-grade pTa and pT1 groups. Both the immunoreaction intensity and positive cells percentage were lower (p<0.01) for TLR4, TRIF, IRF-3, and IFN-γ in the pTis group with respect to other groups. No statistical difference was found between high-grade pTa and pT1 groups for these biomarkers. Likewise, CX3CR1 immunoreactivities were remarkably lower (p<0.01) in the pTis group in comparison with high-grade pTa and pT1 groups, which did not show statistical differences between them. Furthermore, immune checkpoints (PD-1/PD-L1 and CTLA4) and FOXP3+ Treg cells immunoreactivities were significantly higher (p<0.01) in the high-grade pTa and pT1 compared to the pTis group. Conclusions: Our data demonstrated that pTis stage was characterized by an immunosuppressive microenvironment in comparison with pTa and pT1 stages, showing decreased TLR4-mediated interferon signaling pathway and low activation of CX3CR1+CD8+ T-cells; which implies in low sensitivity to immunotherapy. The larger number of FOXP3+ Treg cells in pTa and pT1 was correlated with intensified immune checkpoints immunoreactivities, indicating higher sensitivity to immunotherapy. Finally, these biomarkers may be useful in the clinical management of patients with NMIBC. |
publishDate |
2023 |
dc.date.none.fl_str_mv |
2023-04-27 |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion |
format |
article |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
https://ojs.brazilianjournals.com.br/ojs/index.php/BJHR/article/view/59226 10.34119/bjhrv6n2-307 |
url |
https://ojs.brazilianjournals.com.br/ojs/index.php/BJHR/article/view/59226 |
identifier_str_mv |
10.34119/bjhrv6n2-307 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
https://ojs.brazilianjournals.com.br/ojs/index.php/BJHR/article/view/59226/42936 |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.format.none.fl_str_mv |
application/pdf |
dc.publisher.none.fl_str_mv |
Brazilian Journals Publicações de Periódicos e Editora Ltda. |
publisher.none.fl_str_mv |
Brazilian Journals Publicações de Periódicos e Editora Ltda. |
dc.source.none.fl_str_mv |
Brazilian Journal of Health Review; Vol. 6 No. 2 (2023); 8301-8313 Brazilian Journal of Health Review; Vol. 6 Núm. 2 (2023); 8301-8313 Brazilian Journal of Health Review; v. 6 n. 2 (2023); 8301-8313 2595-6825 reponame:Brazilian Journal of Health Review instname:Federação das Indústrias do Estado do Paraná (FIEP) instacron:BJRH |
instname_str |
Federação das Indústrias do Estado do Paraná (FIEP) |
instacron_str |
BJRH |
institution |
BJRH |
reponame_str |
Brazilian Journal of Health Review |
collection |
Brazilian Journal of Health Review |
repository.name.fl_str_mv |
Brazilian Journal of Health Review - Federação das Indústrias do Estado do Paraná (FIEP) |
repository.mail.fl_str_mv |
|| brazilianjhr@gmail.com |
_version_ |
1797240028953313280 |