Novel immune and stromal subtype classification system of lung adenocarcinoma based on tumor microenvironment

ABSTRACT Background Tumor microenvironment has complex effects on tumorigenesis and metastasis in lung adenocarcinoma (LUAD). However, there is still a lack of comprehensive understanding of the relationship between immune and non-immune stromal characteristics in tumor microenvironment. Patients and methods Eight cohort of 1681 lung caner patients were included in this study. The immune and non-immune stromal signatures of tumor microenvironment were identified by eigendecomposition and extraction algorithms. We developed a novel immune and stromal scoring system to quantify anti-tumor immune and promote-metastasis stromal activation, namely PMBT (prognostic model based on tumor microenvironment) as an R package. Tumors were classified into 4 subtypes according to PMBT system. Comprehensive analysis was performed in different subtypes. Results The 4 subgroups had different mutation landscape, molecular, cellular characteristics and prognosis, which validated by 7 data sets containing 1175 patients. 19% patients was characterized by highly active anti-tumor reaction with high production of immunoactive mediators, immunocyte, low fibroblasts infiltration, low TGF-β, VEGFA, collagen and glucose catabolic, low immune checkpoint per T cell, tumor mutation burden, and favourable overall survival (all, P < 0.05) named high-immune and low-stromal activation subgroup (HL). Cellular paracrine network showed both high humoral and cellular immune interaction in HL group. The low-immune and high-stromal activation group (19%) had opposite characteristics with HL group. Moreover, the PMBT system showed the value to predict overall survival and immunotherapy responses (all, P < 0.05). Conclusions Different molecular, cellular characteristics, mutation landscape and prognosis were discovered in the 4 subgroups. Our classification, PMBT system provided novel insight for clinical monitoring and treatment in LUAD.