Immune evolution from preneoplasia to invasive lung adenocarcinomas and underlying molecular features

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.

Deciphering cell lineage specification of human lung adenocarcinoma with single-cell RNA sequencing

“…S4c–d ). For example, the enrichment of T and B lymphocytes as well as the decline in natural killer (NK) cells and granulocytes during tumor progression, suggesting activation of adaptive immune responses, which is consistent with a previous report that immune evasion may have started as early as the preneoplastic stage 18 . These results illustrate a high level of transcriptomic heterogeneity within LUAD, could be at least partially modulated by the surrounding microenvironment during progression.…”

“…Transcriptional phenotypes in TMs, which are involved in apolipoprotein metabolism, are observed mostly in IA stage. Consistent with recent findings, these alterations in stromal and immune populations cooperatively transformed immune-competent tissues into an immune-suppressive TME during LUAD progression 18 , 48 , 61 . Eventually, we find that MDK and TIMP1 are potential biomarkers to facilitate our understanding of LUAD pathogenesis.…”

Evolutionary metabolic landscape from preneoplasia to invasive lung adenocarcinoma

“…Clinical application of low-dose computed tomography (CT) has contributed to a substantial increase in the detection of pulmonary nodules and a reduction in mortality of lung cancer, however, the high false-positive rate of imaging highlights the need for potent approaches for early detection of high-risk patients 4 . Recent studies have depicted the genomic and immune landscape of these lesions and revealed the molecular events underlying the initiation and progression of LUAD 5 – 10 , which may facilitate early diagnosis and cancer prevention. However, deep insight into the metabolic trajectory from AAH to IAC remains elusive.…”

Gene Expression Profiles of Multiple Synchronous Lesions in Lung Adenocarcinoma

“…However, although the gene expression profiles of ADC in the development of lung cancer have been well investigated [ 12 , 13 ], relatively little is known about the global transcriptome changes associated with AAH [ 6 ]. Moreover, although recent studies have reported suppressed antitumor and enhanced protumor activities related to immune signaling in AAH, as well as sequential changes in immunity-related features across a continuum from preinvasive to advanced lung ADC [ 10 , 16 ], these results require further verification. However, due to the scarcity of tissue samples and the highly diverse genetic background of lung ADC, confirmatory studies are challenging.…”