CSPG4 expression in soft tissue sarcomas is associated with poor prognosis and low cytotoxic immune response

Abstract

Background Soft tissue sarcomas (STS) are heterogeneous and pro-metastatic tumors. Identification of accurate prognostic factors and novel therapeutic targets are crucial. CSPG4 is a cell surface proteoglycan with oncogenic functions. It recently emerged as a potential target for immunotherapy, including cell therapy based on CSPG4-specific chimeric antigen receptor (CAR)-redirected cytokine-induced killer lymphocytes (CSPG4-CAR.CIKs) in STS. However, expression of CSPG4 is poorly known in STS so far. Methods We analyzed CSPG4 gene expression in 1378 localized STS clinical samples, and searched for correlations with clinicopathological data, including disease-free survival (DFS), and with tumor immune features. Results CSPG4 expression was heterogeneous across samples. High expression was associated with younger patients’ age, more frequent undifferentiated pleomorphic sarcoma and myxofibrosarcoma pathological subtypes, more frequent internal trunk tumor site, and more CINSARC high-risk samples. No correlation existed with pathological tumor size and grade, and tumor depth. Patients with high CSPG4 expression displayed 49% (95% CI 42–57) 5-year DFS versus 61% (95% CI 56–68) in patients with low expression (p = 3.17E−03), representing a 49% increased risk of event in the “CSPG4-high” group (HR = 1.49, 95% CI 1.14–1.94). This unfavorable prognostic value persisted in multivariate analysis, independently from other variables. There were significant differences in immune variables between “CSPG4-high” and “CSPG4-low” tumors. The "CSPG4-low" tumors displayed profiles suggesting higher anti-tumor cytotoxic immune response and higher potential vulnerability to immune checkpoint inhibitors (ICI). By contrast, the "CSPG4-high" tumors displayed profiles implying an immune-excluded tumor microenvironment, potentially induced by hypoxia, resulting from an immature chaotic microvasculature, and/or the presence of contractile myofibroblasts. Conclusions Patients with “CSPG4-high” STS, theoretically candidate for CAR.CIKs, display shorter DFS and an immune environment unfavorable to vulnerability to CAR.CIKs, which could be improved by combining anti-angiogenic drugs able to normalize the tumor vasculature. By contrast, “CSPG4-low” STS are better candidates for immune therapy involving ICI.

Prognostic analysis of anoikis-related genes in bladder cancer: An observational study

“…[31] CSPG4 functions as a cell surface proteoglycan and promotes oncogenesis. [32] In BLCA, elevated expression of CSPG4 indicates a poor prognosis. [33] Researchers have found that BLCA tissues that became resistant after treatment with cisplatin and gemcitabine showed a significant increase in CSPG4 expression.…”

Constructing an extracellular matrix-related prognostic model for idiopathic pulmonary fibrosis based on machine learning

“…CSPG4 (Chondroitin Sulfate Proteoglycan 4), also known as NG2 or MCSP, is a transmembrane proteoglycan that is found on the outer layers of various cell types, including pericytes, glial cells, and melanoma cells. It is involved in cell adhesion, migration, and proliferation, as well as regulating the signaling pathways involved in these processes [ 27 ]. CSPG4 is a marker for pericytes, which are cells that play a role in maintaining the stability and function of blood vessels.…”

Prognostic significance and immunoinfiltration analysis of genes associated with epithelial-mesenchymal transition and energy metabolism in bladder urothelial carcinoma

“…Chondroitin sulfate proteoglycan 4 (CSPG4) has been demonstrated to exhibit aberrant expression in various tumor types, including soft tissue sarcoma, squamous cell carcinoma of the head and neck, breast cancer, and anaplastic thyroid cancer. Furthermore, CSPG4 has been shown to play a pivotal role in promoting tumor proliferation and metastasis [22][23][24]. Simultaneously, CSPG4 serves as a promising therapeutic target for cancer.…”