Immunoinformatic analysis of role of tumor microenvironment constituents secreted ligands in breast cancer progression, metastasis, prognosis, survival and development of effective tumor microenvironment directed therapeutic strategy

• Immunoinformatic analysis of gene expression data set of tumour microenvironment cells to identify tumor promoting ligands. • Analysis identified key ligand secreted by TME constituents can interact with receptors present on TAM or stromal cells in autocrine and paracrine manner. • Higher expression of TGFBR2, VEGFR2 and TNFRSF12A is significantly related with increased overall survival indicates that these genes have prognostic significance in case of breast cancer patients. • Identified drugs that can disrupt the ligand-receptor interaction may be crucial for TME targeted therapy. Breast cancer is one of the most prevalent types of cancer in females. Nowadays tumor microenvironment (TME) targeted therapy is under intense focus as novel treatment strategy. This study aims at identifying important secreted ligands from TME constituent cells and their receptors that influence cancer progression and metastasis. Gene expression datasets of TME cells downloaded from NCBI-GEO database. Protein-protein interaction (PPI) network construction, correlation with the pathological stages of breast cancer, survival analysis, drug-gene interaction was performed and immune cell infiltration status analyzed using TIMER. Associations of identified genes with different pathological stages of breast cancer were studied and diagnostic and prognostic roles of the genes assessed. Drug candidates identified that influence expression of target genes or proteins using CTD (Comparative Toxicogenomics Database). Comprehensive in silico and immunoinformatic analysis enabled us to narrow down several target ligands-receptor pairs in breast cancer microenvironment related to increased tumorigenicity. Some of the receptors of these ligands show prognostic value. Five ligand receptor pairs identified, that are significantly associated with the pathological stages of breast cancer and immune cell infiltration in TME. High expression of VEGFR2, TGFBR2 and TNFRSF12A in tumor is positively corelated with increased overall survival. These receptors vary significantly with nodal metastasis status and patients age group. Molecular docking analysis was performed for identified protein ligand pairs. Several drug candidates identified using CTD that targets the ligands and their interaction with TME cells. Identification of these interactions and candidate drugs that can disrupt these junctions may provide novel insight to TME directed therapy.