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Updated: Oct 9, 2025
Skeletal Phenotype Analysis of a Conditional Stat3 Deletion Mouse Model
Published on: July 3, 2020
Thrombospondin-1 induced programmed death-ligand 1-mediated immunosuppression by activating the STAT3 pathway in
Zhuochao Liu1, Junxiang Wen1, Fangqiong Hu1
1Department of Orthopedics, Shanghai Key Laboratory for Prevention and Treatment of Bone and Joint Diseases, Shanghai Institute of Traumatology and Orthopedics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Abstract:
Thrombospondin-1 (TSP1) is generally assumed to suppress the growth of osteosarcoma through inhibiting angiogenesis; however, it is unclear whether TSP1 could affect the antitumor immunity against osteosarcoma. We aimed to explore the immune-related tumor-promoting effects of TSP1 and decipher its underlying mechanism. First, we identified that TSP1 regulated programmed death-ligand 1 (PD-L1) expression, which was related to the CD8+ T cells anergy in osteosarcoma cells. The exact role of PD-L1 in the immunosuppressive effect of TSP1 was then further confirmed by the addition of the PD-L1 neutralizing Ab. With the addition of PD-L1 neutralizing Abs during cocultivation, the inhibition of CD8+ T cells was abolished to a certain extent. Further mechanistic investigations showed that TSP1-induced PD-L1 upregulation was achieved by activation of the signal transducer and activator of transcription 3 (STAT3) pathway. In vivo experiments also indicated that TSP1 overexpression could promote the growth of primary lesions, whereas TSP1 knockdown effectively inhibits the growth of the primary lesion as well as lung metastasis by restoring the antitumor immunity. Thrombospondin-1 knockdown combined with PD-L1 neutralizing Ab achieved a more pronounced antitumor effect. Taken together, our study showed that TSP1 upregulates PD-L1 by activating the STAT3 pathway and, therefore, impairs the antitumor immunity against osteosarcoma.
Insights
Thrombospondin-1 (TSP1) promotes osteosarcoma growth by upregulating PD-L1 via the STAT3 pathway, impairing antitumor immunity. Inhibiting TSP1 or PD-L1 restores immune response against osteosarcoma.
Area of Science:
- Immunology
- Oncology
- Molecular Biology
Background:
- Thrombospondin-1 (TSP1) is known to inhibit osteosarcoma angiogenesis.
- Its role in antitumor immunity against osteosarcoma remains unclear.
Purpose of the Study:
- To investigate the immune-related tumor-promoting effects of TSP1 in osteosarcoma.
- To elucidate the underlying molecular mechanisms of TSP1's impact on antitumor immunity.
Main Methods:
- Assessing TSP1's regulation of programmed death-ligand 1 (PD-L1) expression and its effect on CD8+ T cell anergy.
- Utilizing PD-L1 neutralizing antibodies in co-cultivation experiments.
- Investigating the role of the Signal Transducer and Activator of Transcription 3 (STAT3) pathway.
- Conducting in vivo experiments with TSP1 overexpression and knockdown models.
Main Results:
- TSP1 was found to regulate PD-L1 expression, contributing to CD8+ T cell anergy in osteosarcoma.
- PD-L1 neutralizing antibodies partially abolished TSP1-mediated CD8+ T cell inhibition.
- TSP1-induced PD-L1 upregulation is mediated by the activation of the STAT3 pathway.
- In vivo, TSP1 overexpression promoted tumor growth and metastasis, while TSP1 knockdown inhibited them by restoring antitumor immunity.
- Combined TSP1 knockdown and PD-L1 neutralization yielded enhanced antitumor effects.
Conclusions:
- TSP1 promotes osteosarcoma progression by upregulating PD-L1 through STAT3 activation, thereby suppressing antitumor immunity.
- Targeting TSP1 and PD-L1 represents a potential therapeutic strategy for osteosarcoma.
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