11/6/2023 0 Comments Mia solis affinityWe further leverage whole exome sequencing (WES) 7 and methylation data 8 from the same cohort of IPNs to unravel the genomic and methylation alterations that may impinge on the immune contexture (Supplementary Data 1 and Fig. In the current study, we perform immune gene expression profiling, T cell receptor (TCR) sequencing and multiplex immunofluorescence (mIF) staining on a cohort of resected AAH, AIS, MIA and invasive ADC lesions and paired morphologically normal lung tissues (NL) to delineate the evolution of immune contexture, particularly the T cell landscape, across different stages of early lung ADC pathogenesis. However, the extent to which immunoediting sculpts early carcinogenesis of lung ADC and the underlying genomic and epigenetic alterations associated with these immune features still remain undetermined. Our pilot studies of gene expression and genomic profiling on lung ADC precursors have demonstrated distinct transcriptomic features 6 and progressive genomic evolution along the spectrum of AAH to AIS, MIA, and ADC 7. This has subsequently led to scarcity of adequate materials to investigate the molecular landscape of lung ADC precursors.Ĭarcinogenesis results from progressive accumulation of molecular abnormalities (molecular evolution) and escape from host immune surveillance (immunoediting). These lung nodules are often referred to as indeterminate pulmonary nodules (IPNs) without histologic diagnosis, as the diagnostic yield from biopsy of GGO-predominant nodules is low and surgical resection is not the standard of care. Early-stage lung ADCs and their precursors usually present as lung nodules with distinct radiologic features called ground glass opacity (GGO). The classification of early-stage lung ADC and its precursors has been revised by several professional societies to include a spectrum from atypical adenomatous hyperplasia (AAH), the only recognized preneoplasia to lung ADC, to preinvasive adenocarcinoma in situ (AIS), to micro-invasive lesions termed minimally invasive adenocarcinoma (MIA), and eventually frankly invasive ADC 2, 3, 4, 5. Lung adenocarcinoma (ADC) is the most common histological subtype of lung cancer. In depth understanding of the molecular mechanisms of early lung carcinogenesis may accelerate the development of precise diagnostic as well as effective preventive and therapeutic strategies. However, the outcomes of many randomized clinical trials on primary lung cancer prevention have been disappointing 1, primarily due to our rudimentary knowledge of early phases in lung cancer development. Computed tomography (CT) scan-guided lung cancer screening has demonstrated a reduction of lung cancer mortality by 26–61% 1, underscoring the need for early detection and intervention as a crucial strategy to reduce lung cancer incidence and mortality. 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.ĭespite promising advances in clinical management, lung cancer remains the leading cause of cancer death worldwide, largely due to diagnosis at advanced stages when cures are generally unachievable. 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. 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). The mechanism by which anti-cancer immunity shapes early carcinogenesis of lung adenocarcinoma (ADC) is unknown. Nature Communications volume 12, Article number: 2722 ( 2021) Immune evolution from preneoplasia to invasive lung adenocarcinomas and underlying molecular features
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