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.

Autor: Lee HK; Laboratory of Biochemistry and Immunology, College of Veterinary Medicine, Chungbuk National University, Cheongju, Chungbuk, Republic of Korea., Nam MW; Laboratory of Biochemistry and Immunology, College of Veterinary Medicine, Chungbuk National University, Cheongju, Chungbuk, Republic of Korea., Go RE; Laboratory of Biochemistry and Immunology, College of Veterinary Medicine, Chungbuk National University, Cheongju, Chungbuk, Republic of Korea., Koo J; R&D Center, Autotelic Bio, Inc., Seongnam, Gyeonggi, Republic of Korea., Kim TH; R&D Center, Autotelic Bio, Inc., Seongnam, Gyeonggi, Republic of Korea., Park JE; R&D Center, Autotelic Bio, Inc., Seongnam, Gyeonggi, Republic of Korea. Electronic address: juneui.park@autotelic.co.kr., Choi KC; Laboratory of Biochemistry and Immunology, College of Veterinary Medicine, Chungbuk National University, Cheongju, Chungbuk, Republic of Korea. Electronic address: kchoi@cbu.ac.kr.
Jazyk: angličtina
Zdroj: Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie [Biomed Pharmacother] 2023 Mar; Vol. 159, pp. 114212. Date of Electronic Publication: 2023 Jan 05.
DOI: 10.1016/j.biopha.2022.114212
Abstrakt: 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.
Competing Interests: Conflict of interest statement The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)
Databáze: MEDLINE
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