Unveiling chemotherapy-induced immune landscape remodeling and metabolic reprogramming in lung adenocarcinoma by scRNA-sequencing

Abstract

Neoadjuvant chemotherapy has emerged as a significant therapeutic approach in the management of lung cancer, aiming to improve outcomes through preoperative systemic treatment. However, the mechanisms underlying treatment efficacy and resistance remain largely unknown. In this study, scRNA-seq analysis of tumor samples from nine lung adenocarcinoma (LUAD) patients, including four with surgery alone and five with neoadjuvant chemotherapy, was conducted. Additionally, a series of in vitro and in vivo assays, encompassing flow cytometry, immunofluorescence, seahorse assay, and tumor xenograft models, were employed to validate our findings. A total of 83,622 cells were analyzed, revealing high heterogeneity in cell type composition across different groups. Functional enrichment analysis uncovered significant metabolic reprogramming induced by chemotherapy in both tumor cells and macrophages. Notably, two macrophage subtypes were identified: Anti-mac cells (CD45+CD11b+CD86+) and Pro-mac cells (CD45+CD11b+ARG+), with the proportion of Pro-mac cells significantly increasing in LUAD tissues after neoadjuvant chemotherapy. Pro-mac cells were found to promote tumor growth and angiogenesis while suppressing tumor immunity. Furthermore, analysis of T and B cell remodeling induced by neoadjuvant therapy revealed a more robust immune cytotoxic response against tumor cells. Our investigation illuminates the intricate metabolic reprogramming occurring within the TME of LUAD in response to neoadjuvant chemotherapy. Specifically, our study highlights the discernible impact on the composition and functionality of immune cells, notably macrophages and T cells. These insights not only deepen our understanding of the nuanced interactions within the TME but also open avenues for the development of novel targeted therapeutic interventions for LUAD.