Thrombospondin-1 induces CD8+ T cell exhaustion and immune suppression within the tumor microenvironment of ovarian cancer
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 che...
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BMC
2025-05-01
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| Series: | Journal of Ovarian Research |
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| Online Access: | https://doi.org/10.1186/s13048-025-01668-5 |
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| author | Haiyan Liang Suwei Zhang |
| author_facet | Haiyan Liang Suwei Zhang |
| author_sort | Haiyan Liang |
| collection | DOAJ |
| description | 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 This study positions THBS1 as a key regulator of the OC TME, linking TAM recruitment and polarization to CD8+ 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. |
| format | Article |
| id | doaj-art-2fcc54d7e4f84c68bc388bdf7852b61e |
| institution | OA Journals |
| issn | 1757-2215 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Ovarian Research |
| spelling | doaj-art-2fcc54d7e4f84c68bc388bdf7852b61e2025-08-20T02:15:15ZengBMCJournal of Ovarian Research1757-22152025-05-0118111210.1186/s13048-025-01668-5Thrombospondin-1 induces CD8+ T cell exhaustion and immune suppression within the tumor microenvironment of ovarian cancerHaiyan Liang0Suwei Zhang1Department of Reproductive Medicine, The First Affiliated Hospital of Shantou University Medical CollegeDepartment of Clinical Laboratory, Shantou Central HospitalAbstract 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 This study positions THBS1 as a key regulator of the OC TME, linking TAM recruitment and polarization to CD8+ 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.https://doi.org/10.1186/s13048-025-01668-5Ovarian cancerThrombospondin-1Tumor microenvironmentImmune suppressionT cell exhaustion |
| spellingShingle | Haiyan Liang Suwei Zhang Thrombospondin-1 induces CD8+ T cell exhaustion and immune suppression within the tumor microenvironment of ovarian cancer Journal of Ovarian Research Ovarian cancer Thrombospondin-1 Tumor microenvironment Immune suppression T cell exhaustion |
| title | Thrombospondin-1 induces CD8+ T cell exhaustion and immune suppression within the tumor microenvironment of ovarian cancer |
| title_full | Thrombospondin-1 induces CD8+ T cell exhaustion and immune suppression within the tumor microenvironment of ovarian cancer |
| title_fullStr | Thrombospondin-1 induces CD8+ T cell exhaustion and immune suppression within the tumor microenvironment of ovarian cancer |
| title_full_unstemmed | Thrombospondin-1 induces CD8+ T cell exhaustion and immune suppression within the tumor microenvironment of ovarian cancer |
| title_short | Thrombospondin-1 induces CD8+ T cell exhaustion and immune suppression within the tumor microenvironment of ovarian cancer |
| title_sort | thrombospondin 1 induces cd8 t cell exhaustion and immune suppression within the tumor microenvironment of ovarian cancer |
| topic | Ovarian cancer Thrombospondin-1 Tumor microenvironment Immune suppression T cell exhaustion |
| url | https://doi.org/10.1186/s13048-025-01668-5 |
| work_keys_str_mv | AT haiyanliang thrombospondin1inducescd8tcellexhaustionandimmunesuppressionwithinthetumormicroenvironmentofovariancancer AT suweizhang thrombospondin1inducescd8tcellexhaustionandimmunesuppressionwithinthetumormicroenvironmentofovariancancer |