Signatures of Multi-Omics Reveal Distinct Tumor Immune Microenvironment Contributing to Immunotherapy in Lung Adenocarcinoma

Abstract

BackgroundLung adenocarcinoma (LUAD) contains a variety of genomic and epigenomic abnormalities; the effective tumor markers related to these abnormalities need to be further explored.MethodsClustering analysis was performed based on DNA methylation (MET), DNA copy number variation (CNV), and mRNA expression data, and the differences in survival and tumor immune microenvironment (TIME) between subtypes were compared. Further, we evaluated the signatures in terms of both prognostic value and immunological characteristics.ResultsThere was a positive correlation between MET and CNV in LUAD. Integrative analysis of multi-omics data from 443 samples determined molecular subtypes, iC1 and iC2. The fractions of CD8+ T cells and activated CD4+ T cells were higher, the fraction of Tregs was lower, and the expression level of programmed death-ligand 1 (PD-L1) was higher in iC2 with a poor prognosis showing a higher TIDE score. We selected PTTG1, SLC2A1, and FAM83A as signatures of molecular subtypes to build a prognostic risk model and divided patients into high-risk group and low-risk group representing poor prognosis and good prognosis, respectively, which were validated in 180 patients with LUAD. Further, the low-risk group with lower TIDE score had more infiltrating immune cells. In 100 patients with LUAD, the high-risk group with an immunosuppressive state had a higher expression of PD-L1 and lower counts of CD8+ T cells and dendritic cells.ConclusionsThese findings demonstrated that combined multi-omics data could determine molecular subtypes with significant differences of prognosis and TIME in LUAD and suggested potent utility of the signatures to guide immunotherapy.

Analysis of Genetic Alterations in Ocular Adnexal Mucosa-Associated Lymphoid Tissue Lymphoma With Whole-Exome Sequencing

“…The null finding of such analysis would be inconclusive given the small sample size and lack statistical power. In addition, the neoantigens caused by high frequencies of nonsynonymous mutations can trigger a more robust and long-lasting immune response and strong tumor-infiltrating lymphocytes (TIL) infiltration with tumor eradication ( 51 ). Preclinical studies also supported the idea that tumors showing microsatellite instability-high or a high number of TIL phenotype will be more responsive to checkpoint immunotherapies ( 52 – 54 ).…”

Identification of hub-methylated differentially expressed genes in lung adenocarcinoma and immunotherapy resistance

“…Therefore, our research showed that the p53 and wnt/beta-catenin signaling pathways were related to HLF. FAM83A (family with sequence similarity 83 member A) expression increased in LUAD, related to the late LUAD stage and dismal patient survival (20,21). C2orf40 (Chromosome 2 Open Reading Frame 40, referred to as esophageal cancer-related gene 4 (ECRG4) or augurin), represents one of the tumor suppressors showing hypermethylation in different cancers, such as colorectal cancer (CRC) (22), esophageal cancer (EC), breast cancer (BC) and glioma.…”

The clinicopathological impact of tumor‐associated macrophages in patients with cutaneous malignant melanoma

“…7,8 Macrophages infiltrating the TME are defined as tumor-associated macrophages (TAMs). 9,10 TAMs can polarize into different phenotypes, that is, proinflammatory M1 macrophages (classical type) and antiinflammatory M2 macrophages (alternative type). 11,12 Both phenotypes are involved in tumor-related inflammation.…”