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https://www.arca.fiocruz.br/handle/icict/63283
DNA METHYLATION-BASED DEPICTION OF THE IMMUNE MICROENVIRONMENT AND IMMUNE-ASSOCIATED LONG NON-CODING RNAS IN ORAL CAVITY SQUAMOUS CELL CARCINOMAS
Microambiente imunológico tumoral
LncRNAs
Metilação do DNA
Deconvolução
Author
Affilliation
Department of Clinical Genetics. University Hospital of Southern Denmark-Vejle. Institute of Regional Health Research. University of Southern Denmark. Odense, Denmark / Universidade Estadual Paulista. Instituto de Biociências. Departamento de Ciências Químicas e Biológicas. Botucatu, SP, Brasil.
Centro de Câncer A. C. Camargo. Departamento de Cirurgia de Cabeça e Pescoço e Otorrinolaringologia. São Paulo, SP, Brasil.
Centro Internacional de Pesquisa (CIPE). Centro de Câncer A. C. Camargo. São Paulo, SP, Brasil.
Rosalind and Morris Goodman Cancer Institute. McGill University. Montreal, QC, Canada.
Centro Internacional de Pesquisa (CIPE). Centro de Câncer A. C. Camargo. São Paulo, SP, Brasil.
Department of Clinical Genetics. University Hospital of Southern Denmark-Vejle. Institute of Regional Health Research. University of Southern Denmark. Odense, Denmark.
Centro de Câncer A. C. Camargo. Departamento de Patologia. São Paulo, SP, Brasil.
Universidade Estadual Paulista. Instituto de Biociências. Departamento de Ciências Químicas e Biológicas. Botucatu, SP, Brasil.
Instituto de Tecnologia em Saúde. SENAI CIMATEC. Salvador, BA, Brasil / Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil.
Universidade de São Paulo. Faculdade de Medicina. Departamento de Cirurgia de Cabeça e Pescoço. São Paulo, SP, Brasil.
Centro de Câncer A. C. Camargo. Departamento de Cirurgia de Cabeça e Pescoço e Otorrinolaringologia. São Paulo, SP, Brasil / Universidade de São Paulo. Faculdade de Medicina. Departamento de Cirurgia de Cabeça e Pescoço. São Paulo, SP, Brasil.
Department of Clinical Genetics. University Hospital of Southern Denmark-Vejle. Institute of Regional Health Research. University of Southern Denmark. Odense, Denmark.
Centro de Câncer A. C. Camargo. Departamento de Cirurgia de Cabeça e Pescoço e Otorrinolaringologia. São Paulo, SP, Brasil.
Centro Internacional de Pesquisa (CIPE). Centro de Câncer A. C. Camargo. São Paulo, SP, Brasil.
Rosalind and Morris Goodman Cancer Institute. McGill University. Montreal, QC, Canada.
Centro Internacional de Pesquisa (CIPE). Centro de Câncer A. C. Camargo. São Paulo, SP, Brasil.
Department of Clinical Genetics. University Hospital of Southern Denmark-Vejle. Institute of Regional Health Research. University of Southern Denmark. Odense, Denmark.
Centro de Câncer A. C. Camargo. Departamento de Patologia. São Paulo, SP, Brasil.
Universidade Estadual Paulista. Instituto de Biociências. Departamento de Ciências Químicas e Biológicas. Botucatu, SP, Brasil.
Instituto de Tecnologia em Saúde. SENAI CIMATEC. Salvador, BA, Brasil / Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil.
Universidade de São Paulo. Faculdade de Medicina. Departamento de Cirurgia de Cabeça e Pescoço. São Paulo, SP, Brasil.
Centro de Câncer A. C. Camargo. Departamento de Cirurgia de Cabeça e Pescoço e Otorrinolaringologia. São Paulo, SP, Brasil / Universidade de São Paulo. Faculdade de Medicina. Departamento de Cirurgia de Cabeça e Pescoço. São Paulo, SP, Brasil.
Department of Clinical Genetics. University Hospital of Southern Denmark-Vejle. Institute of Regional Health Research. University of Southern Denmark. Odense, Denmark.
Abstract
Oral cavity squamous cell carcinoma (OSCC) is a complex and dynamic disease characterized by clinicopathological and molecular heterogeneity. Spatial and temporal heterogeneity of cell subpopulations has been associated with cancer progression and implicated in the prognosis and therapy response. Emerging evidence indicates that aberrant epigenetic profiles in OSCC may foster an immunosuppressive tumor microenvironment by modulating the expression of immune-related long non-coding RNAs (lncRNAs). DNA methylation analysis was performed in 46 matched OSCC and normal adjacent tissue samples using a genome-wide platform (Infinium HumanMethylation450 BeadChip). Reference-based computational deconvolution (MethylCIBERSORT) was applied to infer the immune cell composition of the bulk samples. The expression levels of genes encoding immune markers and differentially methylated lncRNAs were investigated using The Cancer Genome Atlas dataset. OSCC specimens presented distinct immune cell composition, including the enrichment of monocyte lineage cells, natural killer cells, cytotoxic T-lymphocytes, regulatory T-lymphocytes, and neutrophils. In contrast, B-lymphocytes, effector T-lymphocytes, and fibroblasts were diminished in tumor samples. The hypomethylation of three immune-associated lncRNAs (MEG3, MIR155HG, and WFDC21P) at individual CpG sites was confirmed by bisulfite-pyrosequencing. Also, the upregulation of a set of immune markers (FOXP3, GZMB, IL10, IL2RA, TGFB, IFNG, TDO2, IDO1, and HIF1A) was detected. The immune cell composition, immune markers alteration, and dysregulation of immune-associated lncRNAs reinforce the impact of the immune microenvironment in OSCC. These concurrent factors contribute to tumor heterogeneity, suggesting that epi-immunotherapy could be an efficient alternative to treat OSCC.
Keywords in Portuguese
Câncer bucalMicroambiente imunológico tumoral
LncRNAs
Metilação do DNA
Deconvolução
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