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A novel cancer therapeutic using thrombospondin 1 in dendritic cells
Tzu-Yang Weng1, Shih-Shien Huang2, Meng-Chi Yen3
1Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan; Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
Abstract:
Induction of thrombospondin 1 (TSP-1) is generally assumed to suppress tumor growth through inhibiting angiogenesis; however, it is less clear how TSP-1 in dendritic cells (DCs) influences tumor progression. We investigated tumor growth and immune mechanism by downregulation of TSP-1 in dendritic cells. Administration of TSP-1 small hairpin RNA (shRNA) through the skin produced anticancer therapeutic effects. Tumor-infiltrating CD4(+) and CD8(+) T cells were increased after the administration of TSP-1 shRNA. The expression of interleukin-12 and interferon-γ in the lymph nodes was enhanced by injection of TSP-1 shRNA. Lymphocytes from the mice injected with TSP-1 shRNA selectively killed the tumor cells, and the cytotoxicity of lymphocytes was abolished by depletion of CD8(+) T cells. Injection of CD11c(+) TSP-1-knockout (TSP-1-KO) bone marrow-derived DCs (BMDCs) delayed tumor growth in tumor-bearing mice. Similarly, antitumor activity induced by TSP-1-KO BMDCs was abrogated by depletion of CD8(+) T cells. In contrast, the administration of shRNAs targeting TSP-2, another TSP family member, did not extend the survival of tumor-bearing mice. Finally, TSP-1 shRNA functioned as an immunotherapeutic adjuvant to augment the therapeutic efficacy of Neu DNA vaccination. Collectively, the downregulation of TSP-1 in DCs produces an effective antitumor response that is opposite to the protumor effects by silencing of TSP-1 within tumor cells.
Insights
Downregulating thrombospondin 1 (TSP-1) in dendritic cells (DCs) enhances anti-tumor immunity. This approach boosts T cell responses and improves therapeutic vaccination, offering a novel cancer treatment strategy.
Area of Science:
- Immunology
- Oncology
- Molecular Biology
Background:
- Thrombospondin 1 (TSP-1) typically inhibits angiogenesis, a process crucial for tumor growth.
- The specific role of TSP-1 within dendritic cells (DCs) in modulating tumor progression remains incompletely understood.
Purpose of the Study:
- To investigate the impact of downregulating TSP-1 in DCs on tumor growth and immune mechanisms.
- To explore the potential of TSP-1 downregulation in DCs as an anticancer therapeutic strategy.
Main Methods:
- Administration of TSP-1 small hairpin RNA (shRNA) via skin application.
- Analysis of tumor-infiltrating lymphocytes (CD4+ and CD8+ T cells).
- Measurement of cytokine expression (interleukin-12 and interferon-γ) and lymphocyte-mediated cytotoxicity.
- Utilizing TSP-1-knockout (TSP-1-KO) bone marrow-derived dendritic cells (BMDCs) in tumor-bearing mice.
- Evaluating TSP-1 shRNA as an adjuvant for cancer vaccination.
Main Results:
- TSP-1 shRNA administration demonstrated anticancer therapeutic effects, increasing tumor-infiltrating CD4+ and CD8+ T cells.
- Enhanced expression of interleukin-12 and interferon-γ was observed in lymph nodes.
- Lymphocytes from treated mice exhibited selective tumor cell killing, dependent on CD8+ T cells.
- Injection of TSP-1-KO BMDCs delayed tumor growth, with antitumor activity abrogated by CD8+ T cell depletion.
- TSP-1 shRNA acted as an effective immunotherapeutic adjuvant, enhancing vaccine efficacy.
Conclusions:
- Downregulation of TSP-1 in dendritic cells elicits a potent antitumor immune response.
- This contrasts with the protumor effects observed when TSP-1 is silenced within tumor cells.
- Targeting TSP-1 in DCs represents a promising strategy for cancer immunotherapy.
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