Potential immunologic and prognostic roles of CHRNA6 in SCLC and pan-cancer.

BACKGROUND

Small cell lung cancer (SCLC) is considered the most malignant subtype of lung cancer, and it has a restricted range of therapeutic choices. The emergence of immunotherapy has offered new possibilities for patients with SCLC. However, the scarcity of clinical specimens has hampered the progress of clinical studies and we still face a shortage of dependable indicators to forecast the effectiveness of immunotherapy for SCLC.

METHODS

In our study, we assessed the ImmuneScore and StromalScore of 81 SCLC samples obtained from the cBioPortal database. By comparing gene expression differences between the high and low immune scores groups, we identified 24 differentially expressed genes. Subsequently, an intersection was performed with genes that exhibited differential expression between normal and SCLC tissues, leading us to isolate the gene CHRNA6. To gain a deeper insight into the possible significance of CHRNA6 in SCLC, we singled out 50 genes that showed the most pronounced positive and negative associations with its expression. We then pinpointed hub genes for subsequent functional enrichment analyses by establishing a protein-protein interactions network. We additionally assessed the link between CHRNA6 expression in SCLC and characteristics of the immune microenvironment, along with the efficacy of immunotherapy, using the CIBERSORT, immunophenoscores (IPS), and tumor immune dysfunction and exclusion (TIDE) algorithms. Furthermore, we confirmed the prognostic impact of CHRNA6 expression in SCLC patients undergoing immunotherapy within a clinical cohort. Lastly, we obtained data from The Cancer Genome Atlas (TCGA) to investigate CHRNA6 expression in various tumors and its associations with genetic alterations, DNA methylation, copy number variation, clinicopathological characteristics, biological processes, immune microenvironment, prognosis, and drug sensitivity.

RESULTS

In SCLC, we found that CHRNA6 function was associated with immune activation pathways such as antigen presentation processing and positive regulation of adaptive immune response, and that CHRNA6 demonstrated a strong correlation with immune cells infiltration. In addition, analysis of the clinical cohort revealed that patients with SCLC who exhibited elevated expression of CHRNA6 experienced better responses to immunotherapy. Our pan-cancer analysis disclosed that the expression of CHRNA6 is dysregulated in a multitude of cancers, potentially due to genetic mutations, copy number gains, and DNA demethylation. The gene set enrichment analysis (GSEA) outcomes indicated that CHRNA6 participates in immune responses and may play a positive immune regulatory role in most cancers. Furthermore, CHRNA6 has been observed to have a notable relationship with immune checkpoints, immunomodulators, immune cell infiltration, patient outcomes, and drug sensitivity across various cancers.

CONCLUSIONS

Our findings indicate that the CHRNA6 may act as a predictive indicator for SCLC patients receiving immunotherapy. The study also uncovers the aberrant expression of CHRNA6 in a range of human cancers and its potential roles in immunology and prognosis, offering novel perspectives for tailored cancer therapies.