Identification of Immune-Related Gene Signatures in Lung Adenocarcinoma and Lung Squamous Cell Carcinoma.

Accumulating evidence indicates that immunotherapy helped to improve the survival and quality-of-life of patients with lung adenocarcinoma (LUAD) or lung squamous cell carcinoma (LUSC) besides chemotherapy and gene targeting treatment. This study aimed to develop immune-related gene signatures in LUAD and LUSC subtypes, respectively. LUAD and LUSC samples were divided into high- and low-abundance groups of immune cell infiltration (Immunity_H and Immunity_L) based on the abundance of immune cell infiltrations. The distribution of immune cells was significantly different between the high- and low-immunity subtypes in LUAD and LUSC samples. The differentially expressed genes (DEGs) between those two groups in LUAD and LUSC contain some key immune-related genes, such as PDL1, PD1, CTLA-4, and HLA families. The DEGs were enriched in multiple immune-related pathways. Furthermore, the seven-immune-related-gene-signature (CD1B, CHRNA6, CLEC12B, CLEC17A, CLNK, INHA, and SLC14A2) prognostic model-based high- and low-risk groups were significantly associated with LUAD overall survival and clinical characteristics. The eight-immune-related-gene-signature (C4BPB, FCAMR, GRAPL, MAP1LC3C, MGC2889, TRIM55, UGT1A1, and VIPR2) prognostic model-based high- and low-risk groups were significantly associated with LUSC overall survival and clinical characteristics. The prognostic models were tested as good ones by receiver operating characteristic, principal component analysis, univariate and multivariate analysis, and nomogram. The verifications of these two immune-related-gene-signature prognostic models showed consistency in the train and test cohorts of LUAD and LUSC. In addition, patients with LUAD in the low-risk group responded better to immunotherapy than those in the high-risk group. This study revealed two reliable immune-related-gene-signature models that were significantly associated with prognosis and tumor microenvironment cell infiltration in LUAD and LUSC, respectively. Evaluation of the integrated characterization of multiple immune-related genes and pathways could help to predict the response to immunotherapy and monitor immunotherapy strategies.

Li N ，Wang J ，Zhan X 《Frontiers in Immunology》

Cancer Stemness-Based Prognostic Immune-Related Gene Signatures in Lung Adenocarcinoma and Lung Squamous Cell Carcinoma.

Cancer stem cells (CSCs) refer to cells with self-renewal capability in tumors. CSCs play important roles in proliferation, metastasis, recurrence, and tumor heterogeneity. This study aimed to identify immune-related gene-prognostic models based on stemness index (mRNAsi) in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC), respectively. X-tile software was used to determine the best cutoff value of survival data in LUAD and LUSC based on mRNAsi. Tumor purity and the scores of infiltrating stromal and immune cells in lung cancer tissues were predicted with ESTIMATE R package. Differentially expressed immune-related genes (DEIRGs) between higher- and lower-mRNAsi subtypes were used to construct prognostic models. mRNAsi was negatively associated with StromalScore, ImmuneScore, and ESTIMATEScore, and was positively associated with tumor purity. LUAD and LUSC samples were divided into higher- and lower-mRNAsi groups with X-title software. The distribution of immune cells was significantly different between higher- and lower-mRNAsi groups in LUAD and LUSC. DEIRGs between those two groups in LUAD and LUSC were enriched in multiple cancer- or immune-related pathways. The network between transcriptional factors (TFs) and DEIRGs revealed potential mechanisms of DEIRGs in LUAD and LUSC. The eight-gene-signature prognostic model (ANGPTL5, CD1B, CD1E, CNTFR, CTSG, EDN3, IL12B, and IL2)-based high- and low-risk groups were significantly related to overall survival (OS), tumor microenvironment (TME) immune cells, and clinical characteristics in LUAD. The five-gene-signature prognostic model (CCL1, KLRC3, KLRC4, CCL23, and KLRC1)-based high- and low-risk groups were significantly related to OS, TME immune cells, and clinical characteristics in LUSC. These two prognostic models were tested as good ones with principal components analysis (PCA) and univariate and multivariate analyses. Tumor T stage, pathological stage, or metastasis status were significantly correlated with DEIRGs contained in prognostic models of LUAD and LUSC. Cancer stemness was not only an important biological process in cancer progression but also might affect TME immune cell infiltration in LUAD and LUSC. The mRNAsi-related immune genes could be potential biomarkers of LUAD and LUSC. Evaluation of integrative characterization of multiple immune-related genes and pathways could help to understand the association between cancer stemness and tumor microenvironment in lung cancer.

Li N ，Li Y ，Zheng P ，Zhan X ... -  《Frontiers in Endocrinology》

Insights into the heterogeneity of the tumor microenvironment in lung adenocarcinoma and squamous carcinoma through single-cell transcriptomic analysis: Implications for distinct immunotherapy outcomes.

Immune checkpoint blockade has emerged as a key strategy to the therapy landscape of non-small cell lung cancer (NSCLC). However, notable differences in immunotherapeutic outcomes exist between the two primary NSCLC subtypes: lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC). This disparity may stem from the tumor immune microenvironment's heterogeneity at the transcriptome level. By integrative analysis of transcriptomic characterization of 38 NSCLC patients by single-cell RNA sequencing, the present study revealed a distinct tumor microenvironment (TME) between LUAD and LUSC, with relevant results further confirmed in bulk transcriptomic and multiplex immunofluorescence (mIF) validation cohort of neoadjuvant immunotherapy patients. LUAD exhibited a more active immune microenvironment compared to LUSC. This included highly expression of HLA I/II in cancer cells, reinforced antigen presentation potential of dendritic cells and enhanced cytotoxic activity observed in T/NK cells. In LUSC, cancer cells highly expressed genes belonging to the aldo-keto reductases, glutathione S-transferases and aldehyde dehydrogenase family, negatively correlating with immunotherapy outcomes in the validation cohort of our center. Further analysis revealed elevated infiltrated cancer-associated fibroblasts (CAFs) in LUSC, which was corroborated in The Cancer Genome Atlas cohort. Corresponding increased infiltration of ADH1B+ CAFs in major pathologic response (MPR) patients and the higher presence of FAP+ CAFs in non-MPR patients were demonstrated by multiplex mIF. Moreover, upregulating immunosuppressive extracellular matrix remodeling was identified in LUSC. These comprehensive analyses advance the understanding of the differences in TME between LUAD and LUSC, offering insights for patient selection and developing subtype-specific treatment strategies.

Fang X ，Li D ，Wan S ，Hu J ，Zhang P ，Jie D ，Chen L ，Jiang G ，Song N ... -  《-》

Identification of specific prognostic markers for lung squamous cell carcinoma based on tumor progression, immune infiltration, and stem index.

Wu R ，Ma R ，Duan X ，Zhang J ，Li K ，Yu L ，Zhang M ，Liu P ，Wang C ... -  《Frontiers in Immunology》

The Combined Detection of Immune Genes for Predicting the Prognosis of Patients With Non-Small Cell Lung Cancer.

Tian WJ ，Liu SS ，Li BR 《-》