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: Lee HK; Laboratory of Biochemistry and Immunology, College of Veterinary Medicine, Chungbuk National University, Cheongju, Chungbuk, 28644, Republic of Korea.; Laboratory Animal Research Center, Chungbuk National University, Cheongju, Chungbuk, Republic of Korea., Ji HJ; Laboratory Animal Research Center, Chungbuk National University, Cheongju, Chungbuk, Republic of Korea., Shin SK; Laboratory Animal Research Center, Chungbuk National University, Cheongju, Chungbuk, Republic of Korea., Koo J; R&D Center, Autotelic Bio, Inc, Seongnam, Gyeonggi, 13486, Republic of Korea., Kim TH; R&D Center, Autotelic Bio, Inc, Seongnam, Gyeonggi, 13486, Republic of Korea., Kim CW; Laboratory of Biochemistry and Immunology, College of Veterinary Medicine, Chungbuk National University, Cheongju, Chungbuk, 28644, Republic of Korea., Seong YH; Laboratory Animal Research Center, Chungbuk National University, Cheongju, Chungbuk, Republic of Korea.; Laboratory of Pharmacology, College of Veterinary Medicine, Chungbuk National University, Cheongju, Chungbuk, Republic of Korea., Park JE; R&D Center, Autotelic Bio, Inc, Seongnam, Gyeonggi, 13486, Republic of Korea. juneui.park@autotelic.co.kr., Choi KC; Laboratory of Biochemistry and Immunology, College of Veterinary Medicine, Chungbuk National University, Cheongju, Chungbuk, 28644, Republic of Korea. kchoi@cbu.ac.kr.
Jazyk: angličtina
Zdroj: Cancer immunology, immunotherapy : CII [Cancer Immunol Immunother] 2022 Sep; Vol. 71 (9), pp. 2213-2226. Date of Electronic Publication: 2022 Jan 31.
DOI: 10.1007/s00262-022-03157-w
Abstrakt: 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.
(© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)
Databáze: MEDLINE
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