Comprehensive pan-cancer analysis reveals EPHB2 is a novel predictive biomarker for prognosis and immunotherapy response.

PURPOSE: Recent studies have increasingly linked Ephrin receptor B2 (EPHB2) to cancer progression. However, comprehensive investigations into the immunological roles and prognostic significance of EPHB2 across various cancers remain lacking. METHODS: We employed various databases and bioinformatics tools to investigate the impact of EPHB2 on prognosis, immune infiltration, genome instability, and response to immunotherapy. Validation of the correlation between EPHB2 expression and M2 macrophages included analyses using bulk and single-cell transcriptomic datasets, spatial transcriptomics, and multi-fluorescence staining. Moreover, we performed cMap web tool to screen for EPHB2-targeted compounds and assessed their potential through molecular docking and dynamics simulations. Additionally, in vitro validation using lung adenocarcinoma (LUAD) cell lines was conducted to confirm the bioinformatics predictions about EPHB2. RESULTS: EPHB2 dysregulation was observed across multiple cancer types, where it demonstrated significant diagnostic and prognostic value. Gene Set Enrichment Analysis (GSEA) indicated that EPHB2 is involved in enhancing cellular proliferation, invasiveness of cancer cells, and modulation of the anti-cancer immune response. Furthermore, it is emerged as a pan-cancer marker for M2 macrophage infiltration, supported by integrated analyses of transcriptomics and multiple fluorescence staining. In LUAD cells, knockdown of EPHB2 expression led to a decrease in both cell proliferation and migratory activity. CONCLUSION: EPHB2 expression may serve as a pivotal indicator of M2 macrophage infiltration, offering vital insights into tumor dynamics and progression across various cancers, including lung adenocarcinoma, highlighting its significant prognostic and therapeutic potential for further exploration.

Multi­omics identification of a signature based on malignant cell-associated ligand-receptor genes for lung adenocarcinoma.

PURPOSE: Lung adenocarcinoma (LUAD) significantly contributes to cancer-related mortality worldwide. The heterogeneity of the tumor immune microenvironment in LUAD results in varied prognoses and responses to immunotherapy among patients. Consequently, a clinical stratification algorithm is necessary and inevitable to effectively differentiate molecular features and tumor microenvironments, facilitating personalized treatment approaches. METHODS: We constructed a comprehensive single-cell transcriptional atlas using single-cell RNA sequencing data to reveal the cellular diversity of malignant epithelial cells of LUAD and identified a novel signature through a computational framework coupled with 10 machine learning algorithms. Our study further investigates the immunological characteristics and therapeutic responses associated with this prognostic signature and validates the predictive efficacy of the model across multiple independent cohorts. RESULTS: We developed a six-gene prognostic model (MYO1E, FEN1, NMI, ZNF506, ALDOA, and MLLT6) using the TCGA-LUAD dataset, categorizing patients into high- and low-risk groups. This model demonstrates robust performance in predicting survival across various LUAD cohorts. We observed distinct molecular patterns and biological processes in different risk groups. Additionally, analysis of two immunotherapy cohorts (N = 317) showed that patients with a high-risk signature responded more favorably to immunotherapy compared to those in the low-risk group. Experimental validation further confirmed that MYO1E enhances the proliferation and migration of LUAD cells. CONCLUSION: We have identified malignant cell-associated ligand-receptor subtypes in LUAD cells and developed a robust prognostic signature by thoroughly analyzing genomic, transcriptomic, and immunologic data. This study presents a novel method to assess the prognosis of patients with LUAD and provides insights into developing more effective immunotherapies.

Causal links between immune cells and asthma: Insights from a Mendelian Randomization analysis.

OBJECTIVES: Recent studies suggest immunophenotypes may play a role in asthma, but their causal relationship has not been thoroughly examined. METHODS: We used single nucleotide polymorphism (SNP)-derived instrumental variables. Summary data from 731 immune cell profiles and asthma cases were analyzed from genome-wide association studies (GWAS) of European populations. Mendelian Randomization (MR) analyses included inverse variance weighted (IVW), weighted median, and MR-Egger methods. Pleiotropy was assessed using the MR-Egger intercept and MR pleiotropy residual sum and outlier (MR-PRESSO) tests. Reverse MR analysis explored bidirectional causation between asthma and immunophenotypes. All statistical analyses were conducted using R software. RESULTS: MR analysis identified 108 immune signatures potentially contributing to asthma. Two immunophenotypes were significantly associated with asthma risk: CD4+ secreting Treg cells in allergic asthma (ORIVW = 1.078; 95% CI: 1.036-1.122; PIVW = 0.0002) and IgD + CD38- %lymphocyte cells in non-allergic asthma (ORIVW = 1.123; 95% CI: 1.057-1.194; PIVW = 0.0002). CONCLUSIONS: This study highlights the causal associations between specific immunophenotypes and asthma risk, providing new insights into asthma pathogenesis.

Causal association between immune cells and lung cancer risk: a two-sample bidirectional Mendelian randomization analysis.

Background: Previous studies have highlighted the crucial role of immune cells in lung cancer development; however, the direct link between immunophenotypes and lung cancer remains underexplored. Methods: We applied two-sample Mendelian randomization (MR) analysis, using genetic variants as instruments to determine the causal influence of exposures on outcomes. This method, unlike traditional randomized controlled trials (RCTs), leverages genetic variants inherited randomly at conception, thus reducing confounding and preventing reverse causation. Our analysis involved three genome-wide association studies to assess the causal impact of 731 immune cell signatures on lung cancer using genetic instrumental variables (IVs). We initially used the standard inverse variance weighted (IVW) method and further validated our findings with three supplementary MR techniques (MR-Egger, weighted median, and MR-PRESSO) to ensure robustness. We also conducted MR-Egger intercept and Cochran's Q tests to assess heterogeneity and pleiotropy. Additionally, reverse MR analysis was performed to explore potential causality between lung cancer subtypes and identified immunophenotypes, using R software for all statistical calculations. Results: Our MR analysis identified 106 immune signatures significantly associated with lung cancer. Notably, we found five suggestive associations across all sensitivity tests (P<0.05): CD25 on IgD- CD24- cells in small cell lung carcinoma (ORIVW =0.885; 95% CI: 0.798-0.983; P IVW =0.022); CD27 on IgD+ CD24+ cells in lung squamous cell carcinoma (ORIVW =1.054; 95% CI: 1.010-1.100; P IVW =0.015); CCR2 on monocyte cells in lung squamous cell carcinoma (ORIVW =0.941; 95% CI: 0.898-0.987; P IVW =0.012); CD123 on CD62L+ plasmacytoid dendritic cells (ORIVW =0.958; 95% CI: 0.924-0.992; P IVW =0.017) as well as on plasmacytoid dendritic cells (ORIVW =0.958; 95% CI: 0.924-0.992; P IVW =0.017) in lung squamous cell carcinoma. Conclusion: This study establishes a significant genomic link between immune cells and lung cancer, providing a robust basis for future clinical research aimed at lung cancer management.

Pembrolizumab for the better treatment of EGFR-mutant T790M-negative advanced lung adenocarcinoma patients than dual treatment of pemetrexed plus platinum after tyrosine kinase inhibitor treatment failure.

BACKGROUND: The treatment of lung cancer patients, especially those with epidermal growth factor receptor (EGFR)-mutant T790M-negative adenocarcinoma, after first- or second-line tyrosine kinase inhibitor (TKI) treatment failure is challenging due to the poor prognosis and limited effectiveness of platinum two-drug chemotherapy or chemotherapy plus anti-angiogenesis therapy. It is well-known that pembrolizumab monotherapy exhibits low toxicity and long-term survival, but it is unknown in these patients. METHODS: From September 2018 to March 2021, 460 patients in Jiangmen Central Hospital were included and 82 patients with disease progression in lung adenocarcinoma who remained T790M-negative on the second biopsy were screened. Two groups were divided according to treatment status, and simple random sampling was performed to obtain 32 cases respectively. The safety of the patients was subsequently evaluated by telephone follow-up. RESULTS: The objective response rate (ORR) and disease control rate (DCR) in the pembrolizumab group were 15.63% and 53.13%. In the chemotherapy group, the ORR was 8.33% and the DCR was 25% (P<0.05). In the pembrolizumab group, the progression-free survival (PFS) [14.65 months, 95% confidence interval (CI): 13.03 to 16.28] was significantly higher than that of the control group (9.54 months, 95% CI: 8.43 to 10.65) (P<0.05). In the univariate analysis, programmed cell death protein 1 ligand (PD-L1) expression, smoking status, gender, and whether first-line chemotherapy was associated with survival. In the multivariate analysis, gender [P=0.001; hazard ratio (HR) 10.98, 95% CI: 2.49-46.67], first-line chemotherapy (P=0.037; HR 4.5, 95% CI: 1.1-4.81), and PD-L1 expression (P=0.039; HR 0.16, 95% CI: 0.04-0.68) were correlated with patient survival. Grade 3 or grade 4 treatment-related adverse events were not found in the pembrolizumab group, while 2 cases of grade 3 or 4 treatment-related adverse events occurred in the control group. CONCLUSIONS: In advanced lung adenocarcinoma patients with EGFR-mutant T790M-negative after TKI treatment, pembrolizumab had a higher ORR and PFS. Pembrolizumab in women with first-line chemotherapy and PD-L1 ≥25% of those patients may have a good response and a low rate of adverse reactions. A multicenter, prospective, evidence-based study of pembrolizumab salvage therapy in those patients is warranted for posterior line treatment.