Differential Infiltration of Immune Cells Driven by Tumor Heterogeneity Reveals Two Immune Subtypes in Lung Adenocarcinoma

Intra-tumoral heterogeneity (ITH) is a critical factor leading to aggressive progression and response to immunotherapy in lung adenocarcinoma (LUAD). However, the relationship between ITH and immune cells in the tumor microenvironment (TME) has not been systematically elucidated. In the present study, we evaluated the ITH status of LUAD samples based on the mutational data obtained from The Cancer Genome Atlas database. First, we identified five key immune pathways with a significantly continuous downtrend among normal, low-heterogeneous, and high-heterogeneous samples and further excavated nine key immune cells related to the key immune pathways and tumor heterogeneity. Then, two immune subtypes were defined by a consensus clustering algorithm based on the infiltration of these immune cells. Differences between these two immune subtypes were remarkable, including alterations of tumor mutation burden and DNA copy number variation at the genomic level, various metabolic pathways, and the different clinical outcome, which was also validated in two independent Gene Expression Omnibus datasets. The results revealed that ITH was significantly associated with prognosis and infiltrating immune cells in the TME. Our study provides novel insights in understanding the relationship between ITH and immune cells and contributes to the immunotherapy of LUAD patients.