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Updated: Oct 5, 2025
Studying TGF-β Signaling and TGF-β-induced Epithelial-to-mesenchymal Transition in Breast Cancer and Normal Cells
Published on: October 27, 2020
Targeting transforming growth factor-β2 by antisense oligodeoxynucleotide accelerates T cell-mediated tumor rejection
Hong Kyu Lee1,2, Hyeong-Jin Ji2, Sang-Kyung Shin2
1Laboratory of Biochemistry and Immunology, College of Veterinary Medicine, Chungbuk National University, Cheongju, Chungbuk, 28644, Republic of Korea.
Abstract:
Transforming growth factor-beta (TGF-β) pathway mediates suppression of antitumor immunity and is associated with poor prognosis in triple-negative breast cancer (TNBC). In this study, we generated a humanized animal model by transplanting human peripheral blood mononuclear cells into immunodeficient mice followed by inoculation of MDA-MB-231 cells and subsequently analyzed the role of TGF-β2 in the interaction between human T cells and human tumor cells. Following reconstitution of the human immune system, inhibition of TGF-β signaling by TGF-β2 antisense oligodeoxynucleotide (TASO) resulted in accelerated tumor growth inhibition. TGF-β2 inhibition also resulted in downregulation of peripheral Foxp3 + regulatory T cells (Treg), whereas no effect was seen in the expression of CD8 + cytotoxic T cells. Analysis of the TASO-treated mice serum revealed elevated levels of human IFN-γ and reduced levels of human IL-10 and TGF-β2. Moreover, TGF-β2 inhibition resulted in increased CD8 + T cell infiltration, whereas the reduced infiltration of Tregs into the tumor partly resulted from decreased expression of CCL22. Decreased intratumoral Tregs facilitated the activation of cytotoxic T cells, associated with increased granzyme B expression. These results indicate that TASO potentiated T cell-mediated antitumor immunity, and it is proposed that TGF-β2 may be a promising target in the immunotherapeutic strategy of TNBC.
Insights
Inhibiting transforming growth factor-beta 2 (TGF-β2) in a humanized triple-negative breast cancer model suppressed regulatory T cells and boosted cytotoxic T cell activity, suggesting TGF-β2 as a therapeutic target.
Area of Science:
- Immunology
- Oncology
- Molecular Biology
Background:
- The transforming growth factor-beta (TGF-β) pathway is implicated in suppressing antitumor immunity, correlating with poor prognosis in triple-negative breast cancer (TNBC).
- Understanding the specific role of TGF-β isoforms, like TGF-β2, in the tumor microenvironment is crucial for developing effective immunotherapies.
Purpose of the Study:
- To investigate the role of TGF-β2 in T cell-mediated antitumor immunity within a humanized TNBC model.
- To evaluate the therapeutic potential of inhibiting TGF-β2 signaling in TNBC.
Main Methods:
- Generation of a humanized TNBC mouse model by transplanting human peripheral blood mononuclear cells and inoculating MDA-MB-231 cells.
- Treatment with TGF-β2 antisense oligodeoxynucleotide (TASO) to inhibit TGF-β signaling.
- Analysis of T cell populations (Tregs, CD8+ T cells), cytokine profiles (IFN-γ, IL-10), and immune cell infiltration in tumor tissues and serum.
Main Results:
- Inhibition of TGF-β2 signaling using TASO led to accelerated tumor growth inhibition.
- TASO treatment downregulated peripheral regulatory T cells (Tregs) and increased CD8+ cytotoxic T cell infiltration into tumors.
- Analysis revealed elevated human IFN-γ and reduced IL-10 and TGF-β2 levels in the serum of TASO-treated mice, alongside increased granzyme B expression in CD8+ T cells.
Conclusions:
- TGF-β2 inhibition potentiates T cell-mediated antitumor immunity in TNBC by reducing Treg infiltration and enhancing cytotoxic T cell activity.
- TGF-β2 represents a promising therapeutic target for immunotherapeutic strategies in triple-negative breast cancer.
