Clinical Significance and Immunologic Landscape of a Five-IL(R)-Based Signature in Lung Adenocarcinoma.

Interleukins (ILs) and interleukin receptors (ILRs) play important role in the antitumor immune response. However, the expression signature and clinical characteristics of the IL(R) family in lung adenocarcinoma (LUAD) remains unclear. The main purpose of this study was to explore the expression profile of IL(R) family genes and construct an IL(R)-based prognostic signature in LUAD. Five public datasets of 1,312 patients with LUAD were enrolled in this study. Samples from The Cancer Genome Atlas (TCGA) were used as the training set, and samples from the other four cohorts extracted from Gene Expression Omnibus (GEO) database were used as the validation set. Additionally, the profile of IL(R) family signature was explored, and the association between this signature and immunotherapy response was also analyzed. Meanwhile, the prognostic value was compared between this IL(R)-based signature and different immunotherapy markers. A signature based on five identified IL(R)s (IL7R, IL5RA, IL20RB, IL11, IL22RA1) was constructed using the TCGA dataset through univariate/multivariable Cox proportional hazards regression and least absolute shrinkage and selection operator (LASSO) Cox analysis. These cases with LUAD were stratified into high- and low-risk group according to the risk score. This signature showed a strong prognostic ability, which was verified by the five independent cohorts and clinical subtypes. The IL(R)-based models presented unique characteristics in terms of immune cell infiltration and immune inflammation profile in tumor microenvironment (TME). Biological pathway analysis confirmed that high-risk patients showed significant T- and B-cell immunosuppression and rapid tumor cell proliferation. More importantly, we researched the relationship between this IL(R)-based signature and immune checkpoints, tumor mutation burden (TMB), tumor purity and ploidy, and tumor immune dysfunction and exclusion (TIDE) score, which confirmed that this signature gave the best prognostic value. We first provided a robust prognostic IL(R)-based signature, which had the potential as a predictor for immunotherapy response to realize individualized treatment of LUAD.

Fan T ，Pan S ，Yang S ，Hao B ，Zhang L ，Li D ，Geng Q ... -  《Frontiers in Immunology》

Comprehensive analysis of a chemokine- and chemokine receptor family-based signature for patients with lung adenocarcinoma.

The clinical significance and comprehensive features of chemokines and their receptors in lung adenocarcinoma (LUAD) have not been clarified. We aimed to characterize the expression profiles of chemokine and chemokine receptor family members and construct a chemokine- and chemokine receptor-based prognosis signature. A total of 1511 patients with LUAD from seven independent cohorts were included in the study. The training set collected from The Cancer Genome Atlas (TCGA) database containing 468 cases. The validation was performed on the basis of six different cohorts downloaded from Gene Expression Omnibus (GEO) database. A five-chemokine- and chemokine receptor-(CXCL2, CXCL13, CCL26, CCL20, CX3CR1) based prognosis signature was constructed with TCGA dataset using LASSO Cox regression and Cox proportional hazards regression analysis. A multivariate analysis verified that this signature was an independent prognostic factor. The predictive value of this signature was further verified by other six independent cohorts and multiple clinical subtypes. We performed immune cell infiltration analysis and biological pathway analysis which provided more insight into this signature-related immune and inflammatory landscape and clarified the intrinsic molecular mechanism by which this signature could be used to predict clinical prognosis. Furthermore, we explored the close relationship between this signature and tumor mutation burden (TMB), neoantigen burden, PD-1, PD-L1, CTLA4, TIDE score, T cell-inflamed score. This signature provided a robust prognostic biomarker for LUAD and could serve as a predictor for immunotherapy response, which may be used as an important supplement to immunotherapy to achieve individualized tumor treatment by optimizing the prognostic management and immunotherapy for patients with LUAD.

Fan T ，Liu Y ，Liu H ，Wang L ，Tian H ，Zheng Y ，Zheng B ，Xue L ，Tan F ，Xue Q ，Gao S ，Li C ，He J ... -  《-》

Profiles of immune infiltration in lung adenocarcinoma and their clinical significant: A gene-expression-based retrospective study.

Chen G ，Dong Z ，Wu D ，Chen Y ... -  《-》

Comprehensive molecular analyses of a TNF family-based signature with regard to prognosis, immune features, and biomarkers for immunotherapy in lung adenocarcinoma.

Tumour Necrosis Factor (TNF) family members play important roles in mounting anti-tumour immune responses, and clinical trials targeting these molecules are ongoing. However, the expression patterns and clinical significance of TNF members in lung adenocarcinoma (LUAD) remain unrevealed. This study aimed to explore the gene expression profiles of TNF family members in LUAD and constructed a TNF family-based prognosis signature. In total, 1300 LUAD cases from seven different cohorts were collected. Samples from The Cancer Genome Atlas (TCGA) were used as the training set, and the RNA data from five Gene Expression Omnibus (GEO) datasets and qPCR data from 102 samples were used for validation. The immune profiles and potential immunotherapy response prediction value of the signature were also explored. After univariate Cox proportional hazards regression and stepwise multivariable Cox analysis, a TNF family-based signature was constructed in the TCGA dataset that significantly stratified cases into high- and low-risk groups in terms of OS. This signature remained an independent prognostic factor in multivariate analyses. Moreover, the clinical significance of the signature was well validated in different clinical subgroups and independent validation cohorts. Further analysis revealed that signature high-risk patients were characterized by distinctive immune cell proportions and immune-suppressive states. Additionally, signature scores were positively related to multiple immunotherapy biomarkers. This was the first TNF family-based model for predicting outcomes and immune landscapes for patients with LUAD. The capability of this signature for predicting immunotherapy response needs further validation.

Zhang C ，Zhang G ，Sun N ，Zhang Z ，Zhang Z ，Luo Y ，Che Y ，Xue Q ，He J ... -  《EBioMedicine》

Combination of tumor mutation burden and immune infiltrates for the prognosis of lung adenocarcinoma.

Tumor mutation burden (TMB) levels are associated with immune infiltrates in the tumor microenvironment and can modulate the responses to immune checkpoint inhibitors (ICIs) in lung adenocarcinoma (LUAD) patients. This study aimed at exploring the potential role of a signature of genes associated with TMB and immune infiltrates and the relevant nomogram in the prognosis of LUAD. The TMB levels in LUAD patients in the Cancer Genome Atlas (TCGA) were analyzed. The differentially expressed genes (DEGs) between the higher- and lower-TMB subgroups were functionally analyzed. The immune-related DEGs and their relationship with immune infiltrates in the tumor environment between two subgroups were analyzed. Nine immune-related DEGs were used to generate a TMB-related immune signature. The sensitivity to immunotherapy in TCGA-LUAD patients was analyzed by immunophenotypic scores (IPS). Subsequently, a nomogram was generated using tumor-related parameters and the signature score. The signature or nomogram values in predicting overall survival (OS) were evaluated and validated in LUAD patients in the GSE30219 and GSE72094. There were 468 DEGs between the higher and lower-TMB subgroups of LUAD patients. The TMB levels were associated positively with the number of immune infiltrates in LUAD patients. Nine DEGs were related to immune infiltrates in the tumor environment. The higher signature scores (high-risk) were associated with poor prognosis of LUAD in the TCGA, which was validated in LUAD patients of the GSE30219 and GSE72094 datasets. Interestingly, the patients in the high-risk group had higher PD-L1 expression in their tumors and the risk scores in LUAD patients. The IPS of LUAD patients in the high-risk group were predicted to benefit from immunotherapy. Finally, the nomogram had high AUC values in predicting the OS of LUAD patients. The TMB-related immune signature or nomogram is valuable for the prognosis of LUAD patients and evaluating their responses to ICIs. These relevant genes may participate into the pathogenesis, ICIs, and drug resistance of LUAD.

Zhao Z ，He B ，Cai Q ，Zhang P ，Peng X ，Zhang Y ，Xie H ，Wang X ... -  《-》