In Situ Overexpression of Matricellular Mechanical Proteins Demands Functional Immune Signature and Mitigates Non-Small Cell Lung Cancer Progression

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dc.contributorSistema FMUSP-HC: Faculdade de Medicina da Universidade de São Paulo (FMUSP) e Hospital das Clínicas da FMUSP
dc.contributor.authorYAEGASHI, Lygia Bertalha
dc.contributor.authorBALDAVIRA, Camila Machado
dc.contributor.authorPRIETO, Tabatha Gutierrez
dc.contributor.authorMACHADO-RUGOLO, Juliana
dc.contributor.authorVELOSA, Ana Paula Pereira
dc.contributor.authorSILVEIRA, Lizandre Keren Ramos da
dc.contributor.authorASSATO, Aline
dc.contributor.authorAB'SABER, Alexandre Muxfeldt
dc.contributor.authorFALZONI, Roberto
dc.contributor.authorTAKAGAKI, Teresa
dc.contributor.authorSILVA, Pedro Leme
dc.contributor.authorTEODORO, Walcy Rosolia
dc.contributor.authorCAPELOZZI, Vera Luiza
dc.date.accessioned2021-10-20T14:02:18Z
dc.date.available2021-10-20T14:02:18Z
dc.date.issued2021
dc.description.abstractNon-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/mm(2). 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/mm(2) and CD3+ <= 278.5 cells/mm(2). 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.eng
dc.description.indexMEDLINEeng
dc.identifier.citationFRONTIERS IN IMMUNOLOGY, v.12, 2021
dc.identifier.doi10.3389/fimmu.2021.714230
dc.identifier.issn1664-3224
dc.identifier.urihttps://observatorio.fm.usp.br/handle/OPI/42384
dc.language.isoeng
dc.publisherFRONTIERS MEDIA SAeng
dc.relation.ispartofFrontiers in Immunology
dc.rightsopenAccesseng
dc.rights.holderCopyright FRONTIERS MEDIA SAeng
dc.subjectlung cancereng
dc.subjectimmune cellseng
dc.subjectcollageneng
dc.subjectcancer-associated fibroblastseng
dc.subjectimmunofluorescenceeng
dc.subjectimmunohistochemistryeng
dc.subjectnon-small cell lung cancereng
dc.subject.othertumor-infiltrating lymphocyteseng
dc.subject.otherregulatory t-cellseng
dc.subject.otherfoxp3 expressioneng
dc.subject.otherclinical-significanceeng
dc.subject.otheraligned collageneng
dc.subject.othermigrationeng
dc.subject.othermicroenvironmenteng
dc.subject.othersurvivaleng
dc.subject.otherclassificationeng
dc.subject.othermacrophageseng
dc.subject.wosImmunologyeng
dc.titleIn Situ Overexpression of Matricellular Mechanical Proteins Demands Functional Immune Signature and Mitigates Non-Small Cell Lung Cancer Progressioneng
dc.typearticleeng
dc.type.categoryoriginal articleeng
dc.type.versionpublishedVersioneng
dspace.entity.typePublication
hcfmusp.author.externalPRIETO, Tabatha Gutierrez:Univ Sao Paulo, Dept Pathol, Med Sch, Sao Paulo, Brazil
hcfmusp.author.externalSILVA, Pedro Leme:Univ Fed Rio de Janeiro, Ctr Ciencias Saude, Carlos Chagas Filho Biophys Inst, Lab Pulm Invest, Rio De Janeiro, Brazil; Natl Inst Sci & Technol Regenerat Med, Rio De Janeiro, Brazil
hcfmusp.citation.scopus3
hcfmusp.contributor.author-fmusphcLYGIA BERTALHA YAEGASHI
hcfmusp.contributor.author-fmusphcCAMILA MACHADO BALDAVIRA
hcfmusp.contributor.author-fmusphcJULIANA MACHADO RUGOLO
hcfmusp.contributor.author-fmusphcANA PAULA PEREIRA VELOSA
hcfmusp.contributor.author-fmusphcLIZANDRE KEREN RAMOS DA SILVEIRA
hcfmusp.contributor.author-fmusphcALINE KAWASSAKI ASSATO
hcfmusp.contributor.author-fmusphcALEXANDRE MUXFELDT AB'SABER
hcfmusp.contributor.author-fmusphcROBERTO FALZONI
hcfmusp.contributor.author-fmusphcTERESA YAE TAKAGAKI
hcfmusp.contributor.author-fmusphcWALCY PAGANELLI ROSOLIA TEODORO
hcfmusp.contributor.author-fmusphcVERA LUIZA CAPELOZZI
hcfmusp.description.volume12
hcfmusp.origemWOS
hcfmusp.origem.pubmed34484217
hcfmusp.origem.scopus2-s2.0-85114374404
hcfmusp.origem.wosWOS:000693493900001
hcfmusp.publisher.cityLAUSANNEeng
hcfmusp.publisher.countrySWITZERLANDeng
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