Work

Thrombospondin-1 induces CD8+ T cell exhaustion and immune suppression within the tumor microenvironment of ovarian cancer

Year: 2025

Type: article

Abstract: BACKGROUND: Ovarian cancer (OC) progression is heavily influenced by the tumor microenvironment (TME), where immune suppression plays a critical role. This study explores the role of thrombospondin-1 (THBS1) in regulating tumor-associated macrophages (TAMs), T cell exhaustion, and immune checkpoint expression, as well as its transcriptional regulation by SNF2H. METHODS: We analyzed THBS1 expression and its clinical significance using publicly available datasets (TCGA-OV, GSE14407) and tissue microarrays containing OC and adjacent normal tissues. In vitro functional studies were conducted using OC cell lines (SKOV3, A2780) and co-cultures with macrophages. Chromatin immunoprecipitation (ChIP) assays and RNA interference were employed to investigate SNF2H-mediated transcriptional regulation of THBS1. In vivo, the role of THBS1 in immune suppression was validated using mouse tumor models. RESULTS: THBS1 was significantly overexpressed in OC tissues and associated with poor prognosis. High levels of THBS1 correlated with increased TAM infiltration, M2 macrophage polarization, and upregulation of immune checkpoints PD-L1 and GAL-3, which contribute to T cell exhaustion. Functional assays demonstrated that THBS1 promotes macrophage recruitment and induces M2 polarization through TGF-β1 and IL-4 signaling. Additionally, ChIP assays identified SNF2H as a transcriptional regulator of THBS1, contributing to its overexpression. In vitro targeting of THBS1 reduced TAM-mediated immune suppression and restored T cell cytotoxicity. CONCLUSION: T cell exhaustion via immune checkpoint modulation. By identifying SNF2H as a transcriptional regulator of THBS1, we offer new insights into its epigenetic dysregulation and suggest potential therapeutic strategies to reprogram the TME and improve the effectiveness of immunotherapy.

Source: Journal of Ovarian Research

DOI: 10.1186/s13048-025-01668-5

Authors: Haiyan Liang, Suwei Zhang

Institutions: Shantou University, First Affiliated Hospital of Shantou University Medical College, Shantou Central Hospital

Language: English

Topic: Cancer Immunotherapy and Biomarkers

Subfield: Oncology

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $3,290