Progression to invasive carcinoma: cellular activities and immune-related pathways define the lepidic and acinar subtypes of lung adenocarcinoma.

Abstract

Lung adenocarcinoma (LUAD) is the most frequent subtype of thoracic malignancy, which is itself the largest contributor to cancer mortality. The lepidic subtype is a non-invasive tumour morphology, whereas the acinar subtype represents one of the invasive morphologies. This study investigates the transition from a non-invasive to an invasive subtype in the context of LUAD. Patients with pathologically confirmed mixed subtype LUAD consented to analysis of RNA sequencing data extracted from each subtype area separately. The study included 17 patients with tumours found to exhibit a lepidic-acinar transition. Eighty-seven genes were found to be differentially expressed between the lepidic and acinar subtypes, with 44 genes significantly upregulated in lepidic samples ​and 43 genes significantly upregulated in acinar samples. Gene Ontology analysis showed that many of the genes upregulated in the acinar subtype were related to immune response, whereas for the lepidic subtype, genes responsible for cellular activities were upregulated. Immune deconvolution analysis showed that there was a significantly higher proportion of M1 macrophages and total B cells in acinar areas. Immunohistochemistry showed that B cells were mainly localised to tertiary lymphoid structures in the tumour area. This is the first study to investigate the molecular features of mixed subtype lepidic-acinar transitional tumours. Immunological dynamics are presumed to be involved in this transition from lepidic to acinar subtype. Further research should be conducted to elucidate the progression of disease from non-invasive to invasive morphologies.