Variants in Epithelial-Mesenchymal Transition and Immune Checkpoint Genes Are Associated With Immune Cell Profiles and Predict Survival in Non-Small Cell Lung Cancer

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dc.contributor.authorParra, Edwin Roger
dc.contributor.authorJiang, Mei
dc.contributor.authorMachado-Rugolo, Juliana
dc.contributor.authorYaegashi, Lygia Bertalha
dc.contributor.authorPrieto, Tabatha
dc.contributor.authorFarhat, Cecilia
dc.contributor.authorSa, Vanessa Karen de [UNESP]
dc.contributor.authorNagai, Maria Aparecida [UNESP]
dc.contributor.authorCordeiro de Lima, Vladmir Claudio
dc.contributor.authorTakagaki, Tereza
dc.contributor.authorTerra, Ricardo
dc.contributor.authorFabro, Alexandre Todorovic
dc.contributor.authorCapelozzi, Vera Luiza
dc.contributor.institutionUniv Texas MD Anderson Canc Ctr
dc.contributor.institutionUniversidade de São Paulo (USP)
dc.contributor.institutionUniversidade Estadual Paulista (Unesp)
dc.contributor.institutionAC Camargo Canc Ctr
dc.contributor.institutionInst Canc Sao Paulo
dc.date.accessioned2021-06-25T12:21:33Z
dc.date.available2021-06-25T12:21:33Z
dc.date.issued2020-10-01
dc.description.abstractContext.-Identification of gene mutations that are indicative of epithelial-mesenchymal transition and a noninflammatory immune phenotype may be important for predicting response to immune checkpoint inhibitors. Objective.-To evaluate the utility of multiplex immunofluorescence for immune profiling and to determine the relationships among tumor immune checkpoint and epithelial-mesenchymal transition genomic profiles and the clinical outcomes of patients with nonmetastatic non-small cell lung cancer. Design.-Tissue microarrays containing 164 primary tumor specimens from patients with stages I to IIIA non-small cell lung carcinoma were examined by multiplex immunofluorescence and image analysis to determine the expression of programmed death ligand-1 (PD-L1) on malignant cells, CD68; macrophages, and cells expressing the immune markers CD3, CD8, CD57, CD45RO, FOXP3, PD-1, and CD20. Immune phenotype data were tested for correlations with clinicopathologic characteristics, somatic and germline genetic variants, and outcome. Results.-A high percentage of PD-L1(+) malignant cells was associated with clinicopathologic characteristics, and high density of CD3+PD-1(+) T cells was associated with metastasis, suggesting that these phenotypes may be clinically useful to identify patients who will likely benefit from immunotherapy. We also found that ZEB2 mutations were a proxy for immunologic ignorance and immune tolerance microenvironments and may predict response to checkpoint inhibitors. A multivariate Cox regression model predicted a lower risk of death for patients with a high density of CD3(+)CD45RO(+) memory T cells, carriers of allele G of CTLA4 variant rs231775, and those whose tumors do not have ZEB2 mutations. Conclusions.-Genetic variants in epithelial mesenchymal transition and immune checkpoint genes are associated with immune cell profiles and may predict patient outcomes and response to immune checkpoint blockade.en
dc.description.affiliationUniv Texas MD Anderson Canc Ctr, Dept Translat Mol Pathol, 1515 Holcombe Blvd,Unit 951, Houston, TX 77030 USA
dc.description.affiliationUniv Sao Paulo, Fac Med, Dept Pathol & Lab Genom & Histomorphometry, Sao Paulo, SP, Brazil
dc.description.affiliationUniv Sao Paulo, Fac Med, Div Pneumol, Heart Inst Incor, Sao Paulo, Brazil
dc.description.affiliationSao Paulo State Univ, Clin Hosp, Fac Med, Dept Oncol, Sao Paulo, Brazil
dc.description.affiliationAC Camargo Canc Ctr, Med Oncol Dept, Sa Paulo, Brazil
dc.description.affiliationAC Camargo Canc Ctr, Translat Immune Oncol Grp, Sa Paulo, Brazil
dc.description.affiliationInst Canc Sao Paulo, Dept Thorac Surg, Sao Paulo, Brazil
dc.description.affiliationHeart Inst Incor, Dept Thorac Surg, Sao Paulo, Brazil
dc.description.affiliationUniv Sao Paulo, Ribeirao Preto Sch Med, Dept Pathol & Legal Med, Ribeirao Preto, Brazil
dc.description.affiliationUnespSao Paulo State Univ, Clin Hosp, Fac Med, Dept Oncol, Sao Paulo, Brazil
dc.description.sponsorshipUniversity of Texas Lung Cancer Specialized Programs of Research Excellence
dc.description.sponsorshipFoundation for the Support of Research of the State of Sao Paulo
dc.description.sponsorshipIdUniversity of Texas Lung Cancer Specialized Programs of Research Excellence: P50CA70907
dc.description.sponsorshipIdFoundation for the Support of Research of the State of Sao Paulo: FAPESP 2013/14277-4
dc.description.sponsorshipIdFoundation for the Support of Research of the State of Sao Paulo: FAPESP 2018-20403-6
dc.format.extent1234-1244
dc.identifierhttp://dx.doi.org/10.5858/arpa.2019-0419-OA
dc.identifier.citationArchives Of Pathology & Laboratory Medicine. Northfield: Coll Amer Pathologists, v. 144, n. 10, p. 1234-1244, 2020.
dc.identifier.doi10.5858/arpa.2019-0419-OA
dc.identifier.issn0003-9985
dc.identifier.urihttp://hdl.handle.net/11449/209539
dc.identifier.wosWOS:000577179300015
dc.language.isoeng
dc.publisherColl Amer Pathologists
dc.relation.ispartofArchives Of Pathology & Laboratory Medicine
dc.sourceWeb of Science
dc.titleVariants in Epithelial-Mesenchymal Transition and Immune Checkpoint Genes Are Associated With Immune Cell Profiles and Predict Survival in Non-Small Cell Lung Canceren
dc.typeArtigo
dcterms.rightsHolderColl Amer Pathologists

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