Purpose Immunoglobulin superfamily 6 (IGSF6) is a novel member of the immunoglobulin superfamily, and the association of IGSF6 with the prognosis and antitumor immune response in lung adenocarcinoma (LUAD) remains unknown. Here, we aim to identify the role of IGSF6-mediated immune signature in the prognosis and immune landscape of LUAD. Methods IGSF6 expression in pan-cancer and LUAD data from The Cancer Genome Atlas (TCGA) was analyzed by TIMER2.0 and GEPIA2, respectively. Quantitative-real-time-PCR (qRT-PCR), western blot, and immunohistochemistry (IHC) staining were performed to confirm the results of bioinformatics. The association of IGSF6 expression and promoter methylation levels with major clinical features was analyzed by using UALCAN. Survival curves were used to assess the connection between IGSF6 expression and LUAD prognosis. The enrichment analysis was conducted by running the R software clusterProfiler package. TISIDB and TIMER2.0 were utilized to investigate the correlation between IGSF6 and tumor-infiltrating lymphocytes (TILs) in LUAD. Human Protein Atlas (HPA) and flow cytometry (FCM) were used to confirm IGSF6 localization in macrophages. Results IGSF6 levels were decreased in LUAD, and methylation levels at the IGSF6 promoter in LUAD samples increased compared to that in peritumor samples, implying a potential mechanism that leads to the aberrant expression of IGSF6 in LUAD. Low IGSF6 expression was significantly related to poor survival. In addition, IGSF6 expression was closely associated with gene sets involved in immune cell proliferation and exogenous antigen presentation, and it was positively related to immune infiltrates with antitumor activity, including M1 macrophages, dendritic cells (DCs), and T helper 1 (Th1). Furthermore, the IGSF6 protein was mainly located on the membrane of macrophages in LUAD, which enabled exogenous antigen presentation by macrophages to enhance the antitumor immune response. Conclusion IGSF6 is a biomarker of LUAD and IGSF6-mediated immune signature determines the prognosis and immune landscape of LUAD.

Background: Immunoglobulin superfamily 6 (IGSF6) is a novel member of the immunoglobulin superfamily, and it is related to multiple diseases. However, the association of IGSF6 with the prognosis and anti-tumor immune response in lung adenocarcinoma (LUAD) remains unknown. Results: By analyzing IGSF6 expression in different cancers based on the pan-cancer data from The Cancer Genome Atlas (TCGA), it was found that IGSF6 expression was decreased in LUAD. Results of quantitative-real-time-PCR (qRT-PCR), western-blot and immunohistochemistry (IHC) staining further confirmed this finding in paired tumor and normal tissues of LUAD patients. Meanwhile, promoter methylation level of IGSF6in LUAD samples increased compared to that in peritumor samples, implying a potential mechanism that leads to the aberrant expression of IGSF6 in LUAD. By estimating the correlation between IGSF6 expression and the prognosis of LUAD, we found that low IGSF6 expression was significantly related to a worse survival rate. The enrichment analysis of IGSF6 co-expression showed that IGSF6 expression was closely associated with gene sets involved in immune cell proliferation and exogenous antigen presentation. In addition, high IGSF6 expression was positively correlated with immune infiltrates with anti-tumor activity, including M1 macropahges, dendritic cells (DCs), and T helper 1 (Th1) cells. Finally, IGSF6 protein was indicated to be mainly located on the membrane of macrophages in LUAD, which might enable exogenous antigen uptake and presentation so as to regulate anti-tumor immune response. Conclusions:IGSF6 is a biomarker for LUAD, which may promote the anti-tumor immune response leading to ameliorative prognosis.