Identification of Three Core Secretome Genes Associated with Immune Infiltration in High Tumor Mutation Burden Across 14 Major Solid Tumors

BACKGROUND: Secretome genes, encoding proteins secreted from the cell, are involved in the tumor immune response and correlated with levels of tumor mutation burden (TMB) in multiple tumors. This study aimed to identify core secretome genes and their potential association with immunomodulators and immune infiltration in high TMB groups across 14 major solid tumors through bioinformatics analysis. METHODS: Multi-omics data for 14 major solid tumors were downloaded from The Cancer Genome Atlas (TCGA) database. Patients were divided into high TMB (TMB-high) and low TMB (TMB-low) groups using the median TMB values for each of the solid tumors. The CIBERSORT algorithm was conducted to estimate the proportion of 22 tumor-infiltrating immune cells (TIICs). Kaplan–Meier analysis and the log-rank test were utilized to screened prognosis-related genes. The correlations between core secretome genes and TIICs were analyzed using Spearman correlation coefficients. RESULTS: In TMB-high groups, multi-omics data analysis revealed that secretome genes were strongly associated with clinical characteristics, and 65 prognosis-related secretome genes were screened. Among the prognosis-related genes, 21 core secretome genes were identified, and strongly associated with five types of TIICs, namely activated NK cells, follicular helper T cells, CD8 T cells, and macrophages M0 and M2. Notably, three secretome genes (ADAMTS12, COL12A1, and COL5A2) were significantly related to immunomodulators and TIICs in multiple solid tumors. In addition, 12 core secretome genes were significantly differentially expressed between responding and non-responding patients receiving immunotherapy. Furthermore, core secretome genes may be involved in the PI3K/AKT signaling pathway. CONCLUSION: We examined the prognostic significance of secretome genes and their potential association with immunomodulators and immune infiltration across 14 major solid tumors. In summary, three secretome genes (ADAMTS12, COL12A1, and COL5A2) may be pivotal mediators of immune infiltration in TMB-high patients, which may help to identify patients who could benefit from immunotherapy.