Immune Subtypes in LUAD Identify Novel Tumor Microenvironment Profiles With Prognostic and Therapeutic Implications

Abstract

The six transcriptomic immune subtypes (ISs) (C1 - C6) were reported to have complex and different interplay between TME and cancer cells in TCGA (The Cancer Genome Atlas) pan-cancer cohort. Our study specifically explored how the consequence of interplay determines the prognosis and the response to therapy in LUAD cohorts. Clinical and molecular information of LUAD patients were from TCGA and Gene Expression Omnibus (GEO). The immune cell populations and gene/pathway enrichment analysis were performed to explore the molecular differences among the C3 IS and other ISs in the LUAD population. The proportion of C3 inflammatory IS was identified as the most common IS in both TCGA (N = 457) and GEO (N = 901) cohorts. The C3 IS was also found to be the most accurate prognostic subtype, which was associated with significantly longer OS (p <0.001) and DFS (p <0.001). The C3 IS presented higher levels of CD8 T, M1 macrophage, and myeloid dendritic cells, while lower levels of M2 macrophages and cancer-associated fibroblast cells. Moreover, the C3 subtype was enriched in the antigen process and presenting, interferon-gamma response, T cell receptor signaling, and natural killer cell-mediated cytotoxicity pathways than C1/C2. In contrast, the C1/C2 presented greater activation of pathways related to the cell cycles, DNA repair, and p53 signaling pathways. The immune-related C3 IS had a great ability to stratify the prognosis of LUAD, providing clues for further pathogenic research. This classification might help direct precision medicine screenings of LUAD patients, thus possibly improving their prognoses.

NSUN2 promotes lung adenocarcinoma progression through stabilizing PIK3R2 mRNA in an m5C‐dependent manner

“…7 LUAD is characterized by biodiversity, a dynamic nature, complex clinical features, and variable clinical prognosis and drug response outcomes, leading to a heterogeneous disease. 8 Although numerous advances in treatments of LUAD, including advances in surgical resection, chemoradiotherapy, molecular targeted therapy, and immunotherapy, the overall survival (OS) of LUAD patients is still poor. 9 Hence, there is a need to illuminate the underlying carcinogenic molecular mechanisms to explore effective diagnostic and therapeutic approaches for LUAD.…”

“…LUAD is often not diagnosed until the cancer is at an advanced stage, leading to a 5‐year survival rate of lower than 15% 7 . LUAD is characterized by biodiversity, a dynamic nature, complex clinical features, and variable clinical prognosis and drug response outcomes, leading to a heterogeneous disease 8 . Although numerous advances in treatments of LUAD, including advances in surgical resection, chemoradiotherapy, molecular targeted therapy, and immunotherapy, the overall survival (OS) of LUAD patients is still poor 9 .…”

In-depth analysis of immune cell landscapes reveals differences between lung adenocarcinoma and lung squamous cell carcinoma

“…Immune cells within the tumor microenvironment can play a dual role in promoting and inhibiting tumor growth, and the imbalance between these opposing forces can impact the outcome of the disease. Immunotherapy has emerged as a promising approach for the treatment of lung cancer in recent years, and understanding the underlying mechanisms of immune dysregulation in this disease is crucial for the development of effective therapies ( 9 ). Therefore, an in-depth investigation of the role of immune dysregulation in lung cancer has significant clinical implications.…”

“…Ecotyper, based on CIBERSORTx, holds advantages such as identifying cell states, estimating their relative abundance in each sample, retrieving them in external expression datasets, and discovering co-association patterns between cell states that make up the cancer ecosystems ( 11 ). Currently, few studies investigated the differences between the two non-small cell lung cancer (NSCLC) subtypes LUAD and LUSC ( 8 , 9 , 12 ). The cell subtypes, cell ratios, and ecotypes have not been comprehensively investigated in LUAD and LUSC.…”

Immune and non-immune cell subtypes identify novel targets for prognostic and therapeutic strategy: A study based on intratumoral heterogenicity analysis of multicenter scRNA-seq datasets in lung adenocarcinoma

“…RNA sequencing (RNA-seq) had already been independently made to predict the prognosis-related genes and assessment their correlation with clinical outcomes in TME. Reports showed immune subtypes in LUAD TME with prognostic and therapeutic implications ( 10 ). Currently, single-cell RNA sequencing (scRNA-seq) is widely used to identify biomarkers in diagnosing, treating patients, and studying the heterogeneity in TME.…”