Targeting transforming growth factor-β2 by antisense oligodeoxynucleotide accelerates T cell-mediated tumor rejection in a humanized mouse model of triple-negative breast cancer
| Autor: | Hyeong-Jin Ji, Sang-Kyung Shin, Jun-Eui Park, Jihye Koo, Tae Hun Kim, Kyung-Chul Choi, Hong Kyu Lee, Cho-Won Kim, Yeon Hee Seong |
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| Rok vydání: | 2022 |
| Předmět: |
Cancer Research
T cell Immunology Triple Negative Breast Neoplasms Biology T-Lymphocytes Regulatory Oligodeoxyribonucleotides Antisense Mice Transforming Growth Factor beta2 Text mining medicine Animals Humans Immunology and Allergy Triple-negative breast cancer Antisense oligodeoxynucleotides business.industry Disease Models Animal medicine.anatomical_structure Oncology Tumor rejection Humanized mouse Cancer research Leukocytes Mononuclear business Transforming growth factor |
| Zdroj: | Cancer Immunology, Immunotherapy. 71:2213-2226 |
| ISSN: | 1432-0851 0340-7004 |
| Popis: | Background: Transforming growth factor (TGF-β) pathway mediates suppression of anti-tumor immunity, and is associated with poor prognosis in triple-negative breast cancer (TNBC). Methods: 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. Results: 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 intra-tumoral Tregs facilitated the activation of cytotoxic T cells, associated with increased granzyme B expression. Conclusion: 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. |
| Databáze: | OpenAIRE |
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