IGSF8 (CD316) defines a distinct transcriptional phenotype independent of immune infiltration in lung adenocarcinoma: An integrative immunogenomic analysis

Background: IGSF8, also known as CD316, is a member of the immunoglobulin superfamily and a transmembrane protein that has recently emerged as a modulator of the innate immune response through natural killer cell checkpoint interactions. Its functions have been considered in various tumors, but its role in lung adenocarcinoma (LUAD) remains undefined. Methods: We performed an integrative analysis of IGSF8 expression in LUAD using transcriptomic and clinical data from The Cancer Genome Atlas (n = 576). IGSF8 expression was analyzed in relation to overall survival, clinical parameters, transcriptomic co-expression, pathway enrichment (via Enrichr), and immune cell infiltration (via xCell). Results: IGSF8 expression did not significantly associate with overall survival in LUAD (log-rank p = 0.693; hazard ratio = 1.16, p = 0.15) and was not correlated with age, gender, or tumor stage. However, enrichment analysis of IGSF8-correlated genes showed a strong association with Notch receptor processing, ephrin signaling, and amyloid-beta formation pathways. Immune cell deconvolution using xCell also did not show any statistically significant differences in infiltration between IGSF8-high and -low tumors. Conclusions: Although not prognostic, IGSF8 may characterize a distinct transcriptional phenotype in LUAD that is characterized by membrane signaling and microenvironmental interactions independent of immune infiltration. These findings warrant further functional studies to explore IGSF8’s potential as an alternative natural killer-cell checkpoint and microenvironmental modulator in LUAD.