Immune Landscape of the Tumor Microenvironment Identifies Prognostic Gene Signature CD4/CD68/CSF1R in Osteosarcoma

Abstract

Background: Osteosarcoma (OSA), the most common primary bone malignancy in children and adolescents, is prone to metastases and unfavorable prognosis. Owing to its strong genomic heterogeneity, traditional chemotherapy, or targeted immunotherapy has not effectively improved the related overall survival for decades. Since the landscape of the OSA tumor immune microenvironment is scarcely known, despite it playing a crucial role in predicting clinical outcomes and therapeutic efficacies, we aimed to elucidate its molecular characteristics. Methods: The immune signature of 101 OSA samples was explored using transcriptome profiling and clinical characteristics retrieved from the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) program. Correlations between the prognostic immune markers and their clinical chemotherapy responses were assessed and verified based on 45 OSA primary tumors. Findings: We identified the heterogeneity underlying tumor immune signature in OSA, and found CD4+ T cells and macrophage markers CD4/IFNGR2/CD68 to be feasible prognostic factors, exerting significantly positive correlation with each other. Specifically, CSF1R, which plays an essential role in the regulation of proliferation and differentiation of macrophages, was found to be a specific signature associated with CD4/CD68, with improved OSA clinical outcomes. Interpretation: The immune landscape based on CD4/CD68/CSF1R gene signatures showed considerable promise for prognostic and therapeutic stratification in OSA patients. A specific immune signature for OSA, abundantly consisting of Th1-polarized CD4+ T cells and CSF1R-related CD68+ macrophages, may improve the predictive efficacy of chemotherapy and improve prognosis in patients with OSA.

Analysis of Immune Gene Expression Subtypes Reveals Osteosarcoma Immune Heterogeneity

“…As not all OS patients have greater benefit from immunotherapy, more immune microenvironment characteristics should be incorporated to instruct clinical treatment. Researchers have made great effort to reveal the role of tumor microenvironment and tumor microenvironment-related genes in OS by a series of bioinformatics methods [ 12 – 14 , 23 , 24 ]. In the present study, the ConsensusClusterPlus algorithm was utilized to identify the five reproducible immune subtypes in 87 OS patients from the TARGET database.…”

“…Zhang et al first established the prognostic signature based on immune microenvironment-related genes for OS [ 14 ], and Hu et al performed comprehensive analysis of prognostic tumor microenvironment-related genes based on several validated genes [ 23 ]. Song et al identified a set of immune gene signature related to clinical response and was verified based on 45 OSA primary tumors [ 12 ]. Our work differs from these studies in several important aspects.…”

“…ese discrepancies may be partially due to their complex and dynamic tumor immune microenvironment where mesenchymal cells, tumor-infiltrating immune cells (TIICs), endothelial cells, extracellular matrix molecules, and inflammatory mediators interact with tumor cells. Although some immune-related gene signature has been recently revealed via bioinformatics analysis [12][13][14], no studies reported a comprehensive immune characterization specifically for OS.…”

Immune classification of osteosarcoma

“…Another set of studies find genes with prognostic values by applying Cox model on survival data or performing differentially expressed genes analysis between two groups of interest, and then investigate the relationship between these genes and estimated immune infiltrates [ 26 – 30 ]. Others study the association of immune abundance with clinical information directly [ 24 , 31 – 34 ]. Our work falls somewhat into the third category.…”

Retinoic acid metabolism-related enzyme signature identified prognostic and immunotherapeutic efficiency in sarcoma

“…For example, the degree of cell-killing T cell in ltration is very low, with only (1.8 cells/HPF) [29]. Devalaraja et al con rmed that sarcoma cells can release RA and promote the differentiation of monocytes in the tumor microenvironment into tumor-associated macrophages in animal models, thereby inhibiting the in ltration of antitumor T-cells [30] and also weakening the clinical effect of immune-checkpoint blockade [31]. This nding was highly recommended by Balkwill for its potential implementation on immunotherapy of sarcomas [32].…”