Abstract
The mechanism by which anti-cancer immunity shapes early carcinogenesis of lung adenocarcinoma (ADC) is unknown. In this study, we characterize the immune contexture of invasive lung ADC and its precursors by transcriptomic immune profiling, T cell receptor (TCR) sequencing and multiplex immunofluorescence (mIF). Our results demonstrate that anti-tumor immunity evolved as a continuum from lung preneoplasia, to preinvasive ADC, minimally-invasive ADC and frankly invasive lung ADC with a gradually less effective and more intensively regulated immune response including down-regulation of immune-activation pathways, up-regulation of immunosuppressive pathways, lower infiltration of cytotoxic T cells (CTLs) and anti-tumor helper T cells (Th), higher infiltration of regulatory T cells (Tregs), decreased T cell clonality, and lower frequencies of top T cell clones in later-stages. Driver mutations, chromosomal copy number aberrations (CNAs) and aberrant DNA methylation may collectively impinge host immune responses and facilitate immune evasion, promoting the outgrowth of fit subclones in preneoplasia into dominant clones in invasive ADC.
Publication types
-
Research Support, N.I.H., Extramural
-
Research Support, Non-U.S. Gov't
-
Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
-
Adenocarcinoma in Situ / genetics*
-
Adenocarcinoma in Situ / immunology
-
Adenocarcinoma in Situ / pathology
-
Adenocarcinoma of Lung / genetics*
-
Adenocarcinoma of Lung / immunology
-
Adenocarcinoma of Lung / pathology
-
Carcinogenesis / genetics*
-
Carcinogenesis / immunology
-
Carcinogenesis / pathology
-
Chromosome Aberrations
-
Clone Cells
-
DNA Copy Number Variations
-
DNA Methylation
-
Gene Expression Profiling
-
Gene Expression Regulation, Neoplastic
-
Humans
-
Immunity, Innate
-
Lung / immunology
-
Lung / metabolism
-
Lung / pathology
-
Lung Neoplasms / genetics*
-
Lung Neoplasms / immunology
-
Lung Neoplasms / pathology
-
Neoplasm Proteins / genetics*
-
Neoplasm Proteins / immunology
-
Precancerous Conditions / genetics*
-
Precancerous Conditions / immunology
-
Precancerous Conditions / pathology
-
Signal Transduction
-
T-Lymphocytes, Cytotoxic / immunology
-
T-Lymphocytes, Cytotoxic / pathology
-
T-Lymphocytes, Helper-Inducer / immunology
-
T-Lymphocytes, Helper-Inducer / pathology
-
T-Lymphocytes, Regulatory / immunology
-
T-Lymphocytes, Regulatory / pathology
-
Transcriptome*
-
Tumor Escape / genetics
-
Tumor Escape / immunology
-
Tumor Microenvironment / genetics
-
Tumor Microenvironment / immunology