IGSF6 is a prognostic biomarker associated with the anti-tumor activity of macrophages in lung adenocarcinoma

Abstract

Background Immunoglobulin superfamily 6 (IGSF6) is a novel member of the immunoglobulin superfamily, and it is related to a variety of human diseases. However, the association of IGSF6 with the prognosis and anti-tumor immune response of lung adenocarcinoma (LUAD) remains unknown. Methods IGSF6 expression in pan-cancer and LUAD data of 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 result of bioinformatics. IGSF6 expression level and promoter methylation level from major clinical features were 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 association of IGSF6 with tumor infiltrating lymphocytes (TILs) in LUAD. Human Protein Atlas (HPA) and flow cytometry (FCM) were used to confirm IGSF6 localization in macrophages. Results IGSF6 expression was decreased in different types of cancers including LUAD. qRT-PCR, western-blot and IHC staining further confirmed this finding in paired tumor and normal tissues of LUAD patients. Meanwhile, promoter methylation level of IGSF6 in 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 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 immune response. Conclusions IGSF6 is a prognostic biomarker for LUAD, which may promote the anti-tumor immune response leading to ameliorative prognosis.