ALCAM-CD6 axis suppression: a key determinant of immune-mediated metastasis recurrence in stage III non-small cell lung cancer.

BACKGROUND: Metastatic recurrence poses a significant challenge in cancer treatment, impacting patient survival and prognosis. Understanding the biological mechanisms behind it is essential for improving treatment strategies and patient outcomes. Lung cancer, the leading cause of cancer-related deaths, is a focus of research for treatment and prognosis. This study specifically targets stage III non-small cell lung cancer (NSCLC) patients following surgery due to their high recurrence variability. METHODS: To delve into the mechanisms of metastatic recurrence in stage III NSCLC patients, we used a comprehensive experimental approach. Long-term follow-up of postoperative patients was combined with single-cell sequencing to uncover tumor microenvironment changes. In vivo and in vitro experiments, including tissue cytometry analysis, real-time PCR, western blotting, gene silencing, cell co-culture, flow cytometry, and chromatin immunoprecipitation-quantitative PCR, were conducted to investigate ALCAM-related gene regulation. Tissue samples and clinical data were collected from stage III NSCLC patients who underwent lung cancer resection between August 2018 and July 2021. RESULTS: Analysis revealed distinct epithelial gene expression patterns between recurrence and non-recurrence groups, highlighting the reduced interaction between ALCAM ligand on epithelial cells and CD6 receptor on T cells. Lower ALCAM levels intensified an immunosuppressive state, halting cell cycle progression and promoting tumor proliferation and migration, linked to metastatic recurrence. The transcription factor MYB was identified as a key ALCAM regulator, shedding light on its impact on tumor advancement. Reduced ALCAM expression correlated with poorer prognosis, offering insights into NSCLC recurrence mechanisms. CONCLUSIONS: Our study underscores the pivotal role of the ALCAM-CD6 axis in metastatic recurrence of stage III NSCLC. ALCAM regulation not only influences immune-tumor cell interactions but also drives tumor cell proliferation and migration by affecting the cell cycle. This finding presents a promising target for NSCLC treatment and aids in assessing patient prognosis effectively.