Abstract
Interferon-induced protein 44-like (IFI44L), a type I interferon-stimulated gene (ISG), has been reported to be involved in innate immune processes and to act as a tumor suppressor in several cancers. However, its immune implication on lung cancer remains unclear. Here, we systemically analyzed the immune association of IFI44L with multiple tumor-infiltrating immune cells (TIICs) and immunomodulators through bioinformatics methods in The Cancer Genome Atlas (TCGA) lung cancer cohorts. Then, the IFI44L-related immunomodulators were selected to construct the prognostic signatures in the lung adenocarcinoma (LUAD) cohort and the lung squamous cell carcinoma (LUSC) cohort, respectively. Concordance index and time-dependent receiver operating characteristics (ROC) curves were applied to evaluate the prognostic signatures. GSE72094 and GSE50081 were used to validate the TCGA-LUAD signature and TCGA-LUSC signature, respectively. A nomogram was established by risk score and clinical features in the LUAD cohort. Finally, the prognostic value and biological function of IFI44L were verified in a real-world cohort and in vitro experiments. The results indicated that IFI44L showed significant correlation with TIICs in LUAD and LUSC samples. Functional enrichment analysis showed that IFI44L may participate in various cancer/immune-related pathways, including JAK/STAT signaling pathway and NF-κB signaling pathway. A total of 44 immunomodulators presented obvious association with IFI44L in the TCGA-LUAD cohort and a robust 10-immunomodulator signature was constructed. Patients in the higher-risk group presented worse prognosis than those in the lower-risk group. Notably, the risk signature was successfully validated in GSE72094. Multivariate Cox regression suggested that the risk signature could act as independent prognostic factors in both TCGA-LUAD and GSE72094 cohorts. Besides, a 17-immunomodulator signature was established in the TCGA-LUSC cohort and similar results were presented through analysis. The nomogram exhibited good accuracy in predicting overall survival (OS) outcome among TCGA-LUAD patients than the risk signature and other clinical features, with the area under curve values being 0.782 at 1 year, 0.825 at 3 years, and 0.792 at 5 years. Finally, tissue microarray analysis indicated that higher expression of IFI44L presented opposite relationship with pathological stage (p = 0.016) and a better outcome among lung cancer patients (p = 0.024). Functional experiments found that IFI44L overexpression significantly inhibited the proliferation, migration, and invasion in LUAD and LUSC cells; RT-qPCR experiments verified the correlation between the expression level of IFI44L with multiple immunomodulators in SPC-A-1 and NCI-H520 cells. In conclusion, our research highlighted that IFI44L is associated with tumor immune infiltration and provided information on IFI44L’s immune implication, which indicates that IFI44L has potential clinical immunotherapeutic value and the proposed nomogram is a promising biomarker for non-small cell lung cancer patients.
Highlights
Lung cancer (LC) is the most common cause of cancer mortality and the second leading cause of morbidity all over the world, accounting for 1,796,144 new deaths (18%) and 2,206,771 new cases (11.4%) in 2020 [1]
The immune implication of Interferon-induced protein 44-like (IFI44L) was explored through various bioinformatics methods, including Tumor IMmune Estimate Resource (TIMER) database analysis, CIBERSORT analysis, and Gene set enrichment analysis (GSEA) and single sample Gene Set Enrichment Analysis (ssGSEA) analysis
These results demonstrated that overexpression of IFI44L can inhibit the growth, migration, and invasion of lung squamous cell carcinoma (LUSC) and lung adenocarcinoma (LUAD) cells, which further proves that IFI44L plays a crucial role in non-small cell lung cancer (NSCLC)
Summary
Lung cancer (LC) is the most common cause of cancer mortality and the second leading cause of morbidity all over the world, accounting for 1,796,144 new deaths (18%) and 2,206,771 new cases (11.4%) in 2020 [1]. From a pathological point of view, LC consists of a group of heterogeneous subtypes, in which the two major types are non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) [2]. Approximately 85% of LC presented with the NSCLC, which can be further divided into lung adenocarcinoma (LUAD), lung squamous cell carcinoma (LUSC), large cell carcinoma, and mixed tissue carcinoma [3]. Despite the advance in treatment methods and strategies, more than 50% of patients died within 1 year after being diagnosed with NSCLC and the 5-year survival rate remains poor [4]. Immunotherapy is becoming an alternative therapeutic approach for cancer patients, especially for NSCLC [5]. Immunotherapy has become the first-line treatment of advanced NSCLC and for consolidation treatment
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