343P Microbiota-derived butyrate potentiates immunotherapy for lung cancer brain metastases by reprogramming CD8+ T cell stemness

Background: The prognostic grading system for invasive lung adenocarcinoma (LUAD) categorizes primary tumors (PT) into five subtypes.Whether cancer cells in lymph node metastasis (LNM) maintain the histological features and genomic evolutionary relationship of their paired PT remains unclear. Methods:We reevaluated tumor histological patterns of the 297 LUAD patients with paired PT and LNM who underwent surgery and targeted sequencing.In three cases, all constituent histological components were isolated via laser-capture microdissection for whole-exome sequencing to explore genomic alterations.Results: Among 297 patients, acinar, papillary, micropapillary, and solid patterns were identified in both PT and LNM, with co-occurrence rates of 60.3%, 31.0%,31.0%,and 31.3%.The solid pattern showed a marked expansion during the metastatic process, emerging as the predominant subtype in 69.7% of LNM.Higher mutation burden, chromosome instability and whole-genome doubling were observed in high-grade (solid/micropapillary) LNM components.Unsupervised clustering based on the specific proportions of each histological component revealed that identical patterns tended to appear simultaneously in the PT and LNM with high quantitative consistency.Subsequent phylogenetic reconstruction confirmed that evolutionary distances were significantly shorter between identical components across sites, suggesting a lineage-specific derivation.Survival analysis showed that high-grade patterns in LNM predicted worse prognosis. Conclusions:Our study characterizes the histological and genomic landscapes of LNM, providing integrated evidence for the histopathologic and genomic origins of metastatic components.These findings emphasize the clinical need to assess histological subtypes within LNM.