TGF-β2 antisense oligonucleotide enhances T-cell mediated anti-tumor activities by IL-2 via attenuation of fibrotic reaction in a humanized mouse model of pancreatic ductal adenocarcinoma
Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive cancers, with high mortality and recurrence rate. In this study, we generated a human immune system mouse model by transplanting human peripheral blood mononuclear cells into NSG-B2m mice followed by xenografting AsPC-1 cells, aft...
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| Format: | Article |
| Language: | English |
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Elsevier
2023-03-01
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| Series: | Biomedicine & Pharmacotherapy |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0753332222016018 |
| _version_ | 1811172197628116992 |
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| author | Hong Kyu Lee Min-Woo Nam Ryeo-Eun Go Jihye Koo Tae Hun Kim Jun-Eui Park Kyung-Chul Choi |
| author_facet | Hong Kyu Lee Min-Woo Nam Ryeo-Eun Go Jihye Koo Tae Hun Kim Jun-Eui Park Kyung-Chul Choi |
| author_sort | Hong Kyu Lee |
| collection | DOAJ |
| description | Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive cancers, with high mortality and recurrence rate. In this study, we generated a human immune system mouse model by transplanting human peripheral blood mononuclear cells into NSG-B2m mice followed by xenografting AsPC-1 cells, after which we assessed the role of transforming growth factor-β2 (TGF-β2) in T-cell-mediated anti-tumor immunity. We observed that inhibiting the TGF-β2 production by TGF-β2 antisense oligonucleotide (TASO) combined with IL-2 delays pancreatic cancer growth. Co-treatment of TASO and IL-2 had little effect on the SMAD-dependent pathway, but significantly inhibited the Akt phosphorylation and sequentially activated GSK-3β. Activation of GSK-3β by TASO subsequently suppressed β-catenin and α-SMA expression and resulted in attenuated fibrotic reactions, facilitating the infiltration of CD8 + cytotoxic T lymphocytes (CTLs) into the tumor. TGF-β2 inhibition suppressed the Foxp3 + regulatory T-cells in peripheral blood and tumors, thereby enhancing the tumoricidal effects of CTLs associated with increased granzyme B and cleaved caspase-3. Moreover, changes in the T-cell composition in peripheral blood and at the tumor site by TASO and IL-2 induced the increase of pro-inflammatory cytokines such as IFN-γ and TNF-α and the decrease of anti-inflammatory cytokines such as TGF-βs. These results indicate that the TGF-β2 inhibition by TASO combined with IL-2 enhances the T-cell mediated anti-tumor immunity against SMAD4-mutated PDAC by modulating the tumor-associated fibrosis, suggesting that TASO in combination with IL-2 may be a promising immunotherapeutic intervention for PDAC. |
| first_indexed | 2024-04-10T17:26:53Z |
| format | Article |
| id | doaj.art-4bd55cf84e11420f81af692f73eef29b |
| institution | Directory Open Access Journal |
| issn | 0753-3322 |
| language | English |
| last_indexed | 2024-04-10T17:26:53Z |
| publishDate | 2023-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Biomedicine & Pharmacotherapy |
| spelling | doaj.art-4bd55cf84e11420f81af692f73eef29b2023-02-04T04:16:57ZengElsevierBiomedicine & Pharmacotherapy0753-33222023-03-01159114212TGF-β2 antisense oligonucleotide enhances T-cell mediated anti-tumor activities by IL-2 via attenuation of fibrotic reaction in a humanized mouse model of pancreatic ductal adenocarcinomaHong Kyu Lee0Min-Woo Nam1Ryeo-Eun Go2Jihye Koo3Tae Hun Kim4Jun-Eui Park5Kyung-Chul Choi6Laboratory of Biochemistry and Immunology, College of Veterinary Medicine, Chungbuk National University, Cheongju, Chungbuk, Republic of KoreaLaboratory of Biochemistry and Immunology, College of Veterinary Medicine, Chungbuk National University, Cheongju, Chungbuk, Republic of KoreaLaboratory of Biochemistry and Immunology, College of Veterinary Medicine, Chungbuk National University, Cheongju, Chungbuk, Republic of KoreaR&D Center, Autotelic Bio, Inc., Seongnam, Gyeonggi, Republic of KoreaR&D Center, Autotelic Bio, Inc., Seongnam, Gyeonggi, Republic of KoreaR&D Center, Autotelic Bio, Inc., Seongnam, Gyeonggi, Republic of Korea; Correspondence to: R&D Center, Autotelic Bio, Inc., Seongnam, Gyeonggi 13486, Republic of Korea.Laboratory of Biochemistry and Immunology, College of Veterinary Medicine, Chungbuk National University, Cheongju, Chungbuk, Republic of Korea; Correspondence to: Laboratory of Biochemistry and Immunology, College of Veterinary Medicine, Chungbuk National University, Cheongju, Chungbuk, 28644, Republic of Korea.Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive cancers, with high mortality and recurrence rate. In this study, we generated a human immune system mouse model by transplanting human peripheral blood mononuclear cells into NSG-B2m mice followed by xenografting AsPC-1 cells, after which we assessed the role of transforming growth factor-β2 (TGF-β2) in T-cell-mediated anti-tumor immunity. We observed that inhibiting the TGF-β2 production by TGF-β2 antisense oligonucleotide (TASO) combined with IL-2 delays pancreatic cancer growth. Co-treatment of TASO and IL-2 had little effect on the SMAD-dependent pathway, but significantly inhibited the Akt phosphorylation and sequentially activated GSK-3β. Activation of GSK-3β by TASO subsequently suppressed β-catenin and α-SMA expression and resulted in attenuated fibrotic reactions, facilitating the infiltration of CD8 + cytotoxic T lymphocytes (CTLs) into the tumor. TGF-β2 inhibition suppressed the Foxp3 + regulatory T-cells in peripheral blood and tumors, thereby enhancing the tumoricidal effects of CTLs associated with increased granzyme B and cleaved caspase-3. Moreover, changes in the T-cell composition in peripheral blood and at the tumor site by TASO and IL-2 induced the increase of pro-inflammatory cytokines such as IFN-γ and TNF-α and the decrease of anti-inflammatory cytokines such as TGF-βs. These results indicate that the TGF-β2 inhibition by TASO combined with IL-2 enhances the T-cell mediated anti-tumor immunity against SMAD4-mutated PDAC by modulating the tumor-associated fibrosis, suggesting that TASO in combination with IL-2 may be a promising immunotherapeutic intervention for PDAC.http://www.sciencedirect.com/science/article/pii/S0753332222016018Pancreatic cancerTGF-β2 antisense oligonucleotideAnticancer immunityHumanized mouse |
| spellingShingle | Hong Kyu Lee Min-Woo Nam Ryeo-Eun Go Jihye Koo Tae Hun Kim Jun-Eui Park Kyung-Chul Choi TGF-β2 antisense oligonucleotide enhances T-cell mediated anti-tumor activities by IL-2 via attenuation of fibrotic reaction in a humanized mouse model of pancreatic ductal adenocarcinoma Biomedicine & Pharmacotherapy Pancreatic cancer TGF-β2 antisense oligonucleotide Anticancer immunity Humanized mouse |
| title | TGF-β2 antisense oligonucleotide enhances T-cell mediated anti-tumor activities by IL-2 via attenuation of fibrotic reaction in a humanized mouse model of pancreatic ductal adenocarcinoma |
| title_full | TGF-β2 antisense oligonucleotide enhances T-cell mediated anti-tumor activities by IL-2 via attenuation of fibrotic reaction in a humanized mouse model of pancreatic ductal adenocarcinoma |
| title_fullStr | TGF-β2 antisense oligonucleotide enhances T-cell mediated anti-tumor activities by IL-2 via attenuation of fibrotic reaction in a humanized mouse model of pancreatic ductal adenocarcinoma |
| title_full_unstemmed | TGF-β2 antisense oligonucleotide enhances T-cell mediated anti-tumor activities by IL-2 via attenuation of fibrotic reaction in a humanized mouse model of pancreatic ductal adenocarcinoma |
| title_short | TGF-β2 antisense oligonucleotide enhances T-cell mediated anti-tumor activities by IL-2 via attenuation of fibrotic reaction in a humanized mouse model of pancreatic ductal adenocarcinoma |
| title_sort | tgf β2 antisense oligonucleotide enhances t cell mediated anti tumor activities by il 2 via attenuation of fibrotic reaction in a humanized mouse model of pancreatic ductal adenocarcinoma |
| topic | Pancreatic cancer TGF-β2 antisense oligonucleotide Anticancer immunity Humanized mouse |
| url | http://www.sciencedirect.com/science/article/pii/S0753332222016018 |
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