Subtype Classification and Prognosis Signature Construction of Osteosarcoma Based on Cellular Senescence-Related Genes

Abstract

Background. Cellular senescence (CS) is an alternative procedure that replaces or reinforces inadequate apoptotic responses and is used as an influencing factor for a variety of cancers. The value of CS gene in evaluating the immunotherapy response and clinical outcome of osteosarcoma (OS) has not been reported, and an accurate risk model based on CS gene has not been developed for OS patients. Methods. 279 CS genes were obtained from CellAge. Univariate Cox regression analysis was used to screen the CS gene which was significantly related to the prognosis of OS samples in TARGET data set. The prognosis, clinicopathological features, immune infiltration, gene expression at immune checkpoints, tumor immune dysfunction and exclusion (TIDE) score, and chemotherapy resistance of OS were analyzed among clusters. Least absolute shrinkage and selection operator (Lasso) Cox regression analysis to build cellular senescence-related gene signature (CSRS). Univariate and multivariate Cox regression analysis of CSRS and clinical parameters were carried out, and the parameters with independent prognostic value were used to construct nomogram. Results. Based on 30 CS genes related to OS prognosis, OS samples were divided into three clusters: C1, C2, and C3. C3 showed the lowest survival rate and metastasis rate and the highest immune score and stromal score and was more likely to respond to immune checkpoint blockade (ICB) treatment. A CSRS scoring system including four CS genes (MYC, DLX2, EPHA3, and LIMK1) was constructed, which could distinguish the survival outcome, tumor microenvironment (TME) status, and ICB treatment response of patients with different CSRS score. Nomogram constructed by CSRS score and metastatic has a high prognostic value for OS. Conclusions. Our study identified a molecular classification determined by CS-related genes and developed a new CSRS that has potential value in OS immunotherapy response and clinical outcome prediction.

Managing the immune microenvironment of osteosarcoma: the outlook for osteosarcoma treatment

“…Osteosarcoma tissue is surrounded by massive immune cell infiltration, resulting in the creation of a complex immune microenvironment that allows osteosarcoma cells to grow within the bone by creating an immunosuppressive microenvironment to maintain their survival and proliferation. [35][36][37] A robust immunosuppressive microenvironment is positively correlated with overactivation of molecules associated with immune suppression, such as indoleamine 2,3-dioxygenase (IDO), programmed cell death protein 1 (PD-1), interleukin-10 (IL-10), transforming growth factor-β (TGF-β), vascular endothelial growth factor (VEGF), and signal transducer and activator of transcription 3 (STAT3), due to their immunosuppressive effects mediated by myeloid-derived suppressor cells (MDSCs), TAMs, and regulatory T lymphocytes (Tregs) [38][39][40][41][42][43] (Fig. 2).…”