In Situ Overexpression of Matricellular Mechanical Proteins Demands Functional Immune Signature and Mitigates Non-Small Cell Lung Cancer Progression
Autor(a) principal: | |
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Data de Publicação: | 2021 |
Outros Autores: | , , , , , , , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Institucional da UNESP |
Texto Completo: | http://dx.doi.org/10.3389/fimmu.2021.714230 http://hdl.handle.net/11449/231502 |
Resumo: | Non-small cell lung carcinoma (NSCLC) is a complex cancer biome composed of malignant cells embedded in a sophisticated tumor microenvironment (TME) combined with different initiating cell types, including immune cells and cancer-associated fibroblasts (CAFs), and extracellular matrix (ECM) proteins. However, little is known about these tumors’ immune-matricellular relationship as functional and mechanical barriers. This study investigated 120 patients with NSCLC to describe the immune-matricellular phenotypes of their TME and their relationship with malignant cells. Immunohistochemistry (IHC) was performed to characterize immune checkpoints (PD-L1, LAG-3, CTLA-4+, VISTA 1), T cells (CD3+), cytotoxic T cells (CD8+, Granzyme B), macrophages (CD68+), regulatory T cells (FOXP3+, CD4+), natural killer cells (CD57+), and B lymphocytes (CD20+), whereas CAFs and collagen types I, III, and V were characterized by immunofluorescence (IF). We observed two distinct functional immune-cellular barriers—the first of which showed proximity between malignant cells and cytotoxic T cells, and the second of which showed distant proximity between non-cohesive nests of malignant cells and regulatory T cells. We also identified three tumor-associated matricellular barriers: the first, with a localized increase in CAFs and a low deposition of Col V, the second with increased CAFs, Col III and Col I fibers, and the third with a high amount of Col fibers and CAFs bundled and aligned perpendicularly to the tumor border. The Cox regression analysis was designed in two steps. First, we investigated the relationship between the immune-matricellular components and tumor pathological stage (I, II, and IIIA), and better survival rates were seen in patients whose tumors expressed collagen type III > 24.89 fibers/mm². Then, we included patients who had progressed to pathological stage IV and found an association between poor survival and tumor VISTA 1 expression > 52.86 cells/mm² and CD3+ ≤ 278.5 cells/mm². We thus concluded that differential patterns in the distribution of immune-matricellular phenotypes in the TME of NSCLC patients could be used in translational studies to predict new treatment strategies and improve patient outcome. These data raise the possibility that proteins with mechanical barrier function in NSCLC may be used by cancer cells to protect them from immune cell infiltration and immune-mediated destruction, which can otherwise be targeted effectively with immunotherapy or collagen therapy. |
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In Situ Overexpression of Matricellular Mechanical Proteins Demands Functional Immune Signature and Mitigates Non-Small Cell Lung Cancer Progressioncancer-associated fibroblastscollagenimmune cellsimmunofluorescenceimmunohistochemistrylung cancernon-small cell lung cancerNon-small cell lung carcinoma (NSCLC) is a complex cancer biome composed of malignant cells embedded in a sophisticated tumor microenvironment (TME) combined with different initiating cell types, including immune cells and cancer-associated fibroblasts (CAFs), and extracellular matrix (ECM) proteins. However, little is known about these tumors’ immune-matricellular relationship as functional and mechanical barriers. This study investigated 120 patients with NSCLC to describe the immune-matricellular phenotypes of their TME and their relationship with malignant cells. Immunohistochemistry (IHC) was performed to characterize immune checkpoints (PD-L1, LAG-3, CTLA-4+, VISTA 1), T cells (CD3+), cytotoxic T cells (CD8+, Granzyme B), macrophages (CD68+), regulatory T cells (FOXP3+, CD4+), natural killer cells (CD57+), and B lymphocytes (CD20+), whereas CAFs and collagen types I, III, and V were characterized by immunofluorescence (IF). We observed two distinct functional immune-cellular barriers—the first of which showed proximity between malignant cells and cytotoxic T cells, and the second of which showed distant proximity between non-cohesive nests of malignant cells and regulatory T cells. We also identified three tumor-associated matricellular barriers: the first, with a localized increase in CAFs and a low deposition of Col V, the second with increased CAFs, Col III and Col I fibers, and the third with a high amount of Col fibers and CAFs bundled and aligned perpendicularly to the tumor border. The Cox regression analysis was designed in two steps. First, we investigated the relationship between the immune-matricellular components and tumor pathological stage (I, II, and IIIA), and better survival rates were seen in patients whose tumors expressed collagen type III > 24.89 fibers/mm². Then, we included patients who had progressed to pathological stage IV and found an association between poor survival and tumor VISTA 1 expression > 52.86 cells/mm² and CD3+ ≤ 278.5 cells/mm². We thus concluded that differential patterns in the distribution of immune-matricellular phenotypes in the TME of NSCLC patients could be used in translational studies to predict new treatment strategies and improve patient outcome. These data raise the possibility that proteins with mechanical barrier function in NSCLC may be used by cancer cells to protect them from immune cell infiltration and immune-mediated destruction, which can otherwise be targeted effectively with immunotherapy or collagen therapy.Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ)Department of Pathology University of São Paulo Medical SchoolHealth Technology Assessment Center (NATS) Clinical Hospital (HCFMB) Medical School of São Paulo State University (UNESP)Rheumatology Division of the Hospital das Clinicas University of São Paulo Medical SchoolDivision of Pneumology Instituto do Coração (Incor) University of São Paulo Medical School (USP)Laboratory of Pulmonary Investigation Carlos Chagas Filho Biophysics Institute Federal University of Rio de Janeiro Centro de Ciências da SaúdeNational Institute of Science and Technology for Regenerative MedicineHealth Technology Assessment Center (NATS) Clinical Hospital (HCFMB) Medical School of São Paulo State University (UNESP)CAPES: 001FAPESP: 2018/20403-6CNPq: 483005/2012-6Universidade de São Paulo (USP)Universidade Estadual Paulista (UNESP)Centro de Ciências da SaúdeNational Institute of Science and Technology for Regenerative MedicineYaegashi, Lygia BertalhaBaldavira, Camila MachadoPrieto, Tabatha GutierrezMachado-Rugolo, Juliana [UNESP]Velosa, Ana Paula Pereirada Silveira, Lizandre Keren RamosAssato, AlineAb’Saber, Alexandre MuxfeldtFalzoni, RobertoTakagaki, TeresaSilva, Pedro LemeTeodoro, Walcy RosoliaCapelozzi, Vera Luiza2022-04-29T08:45:51Z2022-04-29T08:45:51Z2021-08-16info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articlehttp://dx.doi.org/10.3389/fimmu.2021.714230Frontiers in Immunology, v. 12.1664-3224http://hdl.handle.net/11449/23150210.3389/fimmu.2021.7142302-s2.0-85114374404Scopusreponame:Repositório Institucional da UNESPinstname:Universidade Estadual Paulista (UNESP)instacron:UNESPengFrontiers in Immunologyinfo:eu-repo/semantics/openAccess2024-09-03T13:18:13Zoai:repositorio.unesp.br:11449/231502Repositório InstitucionalPUBhttp://repositorio.unesp.br/oai/requestrepositoriounesp@unesp.bropendoar:29462024-09-03T13:18:13Repositório Institucional da UNESP - Universidade Estadual Paulista (UNESP)false |
dc.title.none.fl_str_mv |
In Situ Overexpression of Matricellular Mechanical Proteins Demands Functional Immune Signature and Mitigates Non-Small Cell Lung Cancer Progression |
title |
In Situ Overexpression of Matricellular Mechanical Proteins Demands Functional Immune Signature and Mitigates Non-Small Cell Lung Cancer Progression |
spellingShingle |
In Situ Overexpression of Matricellular Mechanical Proteins Demands Functional Immune Signature and Mitigates Non-Small Cell Lung Cancer Progression Yaegashi, Lygia Bertalha cancer-associated fibroblasts collagen immune cells immunofluorescence immunohistochemistry lung cancer non-small cell lung cancer |
title_short |
In Situ Overexpression of Matricellular Mechanical Proteins Demands Functional Immune Signature and Mitigates Non-Small Cell Lung Cancer Progression |
title_full |
In Situ Overexpression of Matricellular Mechanical Proteins Demands Functional Immune Signature and Mitigates Non-Small Cell Lung Cancer Progression |
title_fullStr |
In Situ Overexpression of Matricellular Mechanical Proteins Demands Functional Immune Signature and Mitigates Non-Small Cell Lung Cancer Progression |
title_full_unstemmed |
In Situ Overexpression of Matricellular Mechanical Proteins Demands Functional Immune Signature and Mitigates Non-Small Cell Lung Cancer Progression |
title_sort |
In Situ Overexpression of Matricellular Mechanical Proteins Demands Functional Immune Signature and Mitigates Non-Small Cell Lung Cancer Progression |
author |
Yaegashi, Lygia Bertalha |
author_facet |
Yaegashi, Lygia Bertalha Baldavira, Camila Machado Prieto, Tabatha Gutierrez Machado-Rugolo, Juliana [UNESP] Velosa, Ana Paula Pereira da Silveira, Lizandre Keren Ramos Assato, Aline Ab’Saber, Alexandre Muxfeldt Falzoni, Roberto Takagaki, Teresa Silva, Pedro Leme Teodoro, Walcy Rosolia Capelozzi, Vera Luiza |
author_role |
author |
author2 |
Baldavira, Camila Machado Prieto, Tabatha Gutierrez Machado-Rugolo, Juliana [UNESP] Velosa, Ana Paula Pereira da Silveira, Lizandre Keren Ramos Assato, Aline Ab’Saber, Alexandre Muxfeldt Falzoni, Roberto Takagaki, Teresa Silva, Pedro Leme Teodoro, Walcy Rosolia Capelozzi, Vera Luiza |
author2_role |
author author author author author author author author author author author author |
dc.contributor.none.fl_str_mv |
Universidade de São Paulo (USP) Universidade Estadual Paulista (UNESP) Centro de Ciências da Saúde National Institute of Science and Technology for Regenerative Medicine |
dc.contributor.author.fl_str_mv |
Yaegashi, Lygia Bertalha Baldavira, Camila Machado Prieto, Tabatha Gutierrez Machado-Rugolo, Juliana [UNESP] Velosa, Ana Paula Pereira da Silveira, Lizandre Keren Ramos Assato, Aline Ab’Saber, Alexandre Muxfeldt Falzoni, Roberto Takagaki, Teresa Silva, Pedro Leme Teodoro, Walcy Rosolia Capelozzi, Vera Luiza |
dc.subject.por.fl_str_mv |
cancer-associated fibroblasts collagen immune cells immunofluorescence immunohistochemistry lung cancer non-small cell lung cancer |
topic |
cancer-associated fibroblasts collagen immune cells immunofluorescence immunohistochemistry lung cancer non-small cell lung cancer |
description |
Non-small cell lung carcinoma (NSCLC) is a complex cancer biome composed of malignant cells embedded in a sophisticated tumor microenvironment (TME) combined with different initiating cell types, including immune cells and cancer-associated fibroblasts (CAFs), and extracellular matrix (ECM) proteins. However, little is known about these tumors’ immune-matricellular relationship as functional and mechanical barriers. This study investigated 120 patients with NSCLC to describe the immune-matricellular phenotypes of their TME and their relationship with malignant cells. Immunohistochemistry (IHC) was performed to characterize immune checkpoints (PD-L1, LAG-3, CTLA-4+, VISTA 1), T cells (CD3+), cytotoxic T cells (CD8+, Granzyme B), macrophages (CD68+), regulatory T cells (FOXP3+, CD4+), natural killer cells (CD57+), and B lymphocytes (CD20+), whereas CAFs and collagen types I, III, and V were characterized by immunofluorescence (IF). We observed two distinct functional immune-cellular barriers—the first of which showed proximity between malignant cells and cytotoxic T cells, and the second of which showed distant proximity between non-cohesive nests of malignant cells and regulatory T cells. We also identified three tumor-associated matricellular barriers: the first, with a localized increase in CAFs and a low deposition of Col V, the second with increased CAFs, Col III and Col I fibers, and the third with a high amount of Col fibers and CAFs bundled and aligned perpendicularly to the tumor border. The Cox regression analysis was designed in two steps. First, we investigated the relationship between the immune-matricellular components and tumor pathological stage (I, II, and IIIA), and better survival rates were seen in patients whose tumors expressed collagen type III > 24.89 fibers/mm². Then, we included patients who had progressed to pathological stage IV and found an association between poor survival and tumor VISTA 1 expression > 52.86 cells/mm² and CD3+ ≤ 278.5 cells/mm². We thus concluded that differential patterns in the distribution of immune-matricellular phenotypes in the TME of NSCLC patients could be used in translational studies to predict new treatment strategies and improve patient outcome. These data raise the possibility that proteins with mechanical barrier function in NSCLC may be used by cancer cells to protect them from immune cell infiltration and immune-mediated destruction, which can otherwise be targeted effectively with immunotherapy or collagen therapy. |
publishDate |
2021 |
dc.date.none.fl_str_mv |
2021-08-16 2022-04-29T08:45:51Z 2022-04-29T08:45:51Z |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
format |
article |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://dx.doi.org/10.3389/fimmu.2021.714230 Frontiers in Immunology, v. 12. 1664-3224 http://hdl.handle.net/11449/231502 10.3389/fimmu.2021.714230 2-s2.0-85114374404 |
url |
http://dx.doi.org/10.3389/fimmu.2021.714230 http://hdl.handle.net/11449/231502 |
identifier_str_mv |
Frontiers in Immunology, v. 12. 1664-3224 10.3389/fimmu.2021.714230 2-s2.0-85114374404 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
Frontiers in Immunology |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.source.none.fl_str_mv |
Scopus reponame:Repositório Institucional da UNESP instname:Universidade Estadual Paulista (UNESP) instacron:UNESP |
instname_str |
Universidade Estadual Paulista (UNESP) |
instacron_str |
UNESP |
institution |
UNESP |
reponame_str |
Repositório Institucional da UNESP |
collection |
Repositório Institucional da UNESP |
repository.name.fl_str_mv |
Repositório Institucional da UNESP - Universidade Estadual Paulista (UNESP) |
repository.mail.fl_str_mv |
repositoriounesp@unesp.br |
_version_ |
1810021405853483008 |