Lung adenocarcinoma is the most frequent subtype of thoracic malignancy, which is itself the largest contributor to cancer mortality. The lepidic subtype is a non-invasive tumor 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 lung adenocarcinoma. Patients with pathologically confirmed mixed subtype tumors consented to analysis of RNA-seq data extracted from each subtype area separately. The study included 17 patients with tumors found to exhibit a lepidic-acinar transition. 87 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. 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 localized to tertiary lymphoid structures in the tumor area. This is the first study to investigate the molecular features of mixed subtype lepidic-acinar transitional tumors. 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.

Dr. Yuka Kitamura is a shareholder and CEO of N Lab Co., Ltd.

All authors declare that they have no conflicts of interest. Funding provided by the New Energy and Industrial Technology Development Organization [grant number JPNP20006], who had no role in study design, collection, analysis and interpretation of data, writing of the report, or in the decision to submit the article for publication.

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The Medical Research Ethics Committee of Tokyo Medical and Dental University (M2021-315; July 26th, 2022) gave ethical approval for this work.

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Data is available upon reasonable request from the corresponding author.