IL-10RA governor the expression of IDO in the instruction of lymphocyte immunity.

Autor: Tai TS; Department of Medical Research and Development, Chang Gung Memorial Hospital, Taoyuan, Taiwan., Hsu DW; Department of Biotechnology, National Kaohsiung Normal University, Kaohsiung City, Taiwan., Yang YS; National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Miaoli, Taiwan.; Institute of Bioinformatics and Structural Biology, National Tsing Hua University, Hsinchu, Taiwan., Tsai CY; Transgenic Core Facility, Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan., Shi JW; Department of Biotechnology, National Kaohsiung Normal University, Kaohsiung City, Taiwan.; National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Miaoli, Taiwan., Wu CH; Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan., Hsu SC; National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Miaoli, Taiwan. mschsu@nhri.edu.tw.; Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung City, Taiwan. mschsu@nhri.edu.tw.; Graduate Institute of Biomedical Science, Immunology Research and Development Center, China Medical University, Taichung City, Taiwan. mschsu@nhri.edu.tw.; Department of Biomedical Sciences and Engineering, Tzu Chi University, Hualien, Taiwan. mschsu@nhri.edu.tw.; Doctoral Program in Tissue Engineering and Regenerative Medicine, National Chung Hsing University, Taichung City, Taiwan. mschsu@nhri.edu.tw.
Jazyk: angličtina
Zdroj: British journal of cancer [Br J Cancer] 2024 Nov 26. Date of Electronic Publication: 2024 Nov 26.
DOI: 10.1038/s41416-024-02893-3
Abstrakt: Background: Indoleamine 2,3-dioxygenase (IDO) impairs anti-pathogen and anti-tumour immunity. Mesenchymal stem cells (MSCs) modulate immunity via IDO but also suppress IFN-γ. While MSC IDO induction by IFN-γ is established, other drivers in this immunosuppressive setting remain unknown.
Methods: Human bone marrow mesenchymal stem cells (MSCs) with IDO or IL-10RA knockdown were co-cultured with healthy donor T cells to assess immunosuppression. PDAC organoid anticancer activity was also tested in these co-cultures.
Results: Co-culturing MSCs with T cells in an IL-10RA-enriched environment enhances IDO expression, resulting in T cell suppression. Moreover, IL-10RA-positive MSCs collected from co-cultures with IL-10 supplementation show increased IDO expression. Conversely, MSCs with IL-10RA knockdown exhibit a significant reduction in IDO RNA and protein expression, as well as STAT3 phosphorylation status, which is a known upstream signalling pathway in IDO gene regulation, in T cell co-cultures. Down-regulation of IL-10RA also inhibits IDO activity in MSCs, resulting in reduced T cell suppression, and enabling the co-cultured T cells to kill PDAC organoids.
Conclusion: Our research reveals IL-10RA as a pharmacological target in stromal cells for enhancing T cell-mediated PDAC eradication by downregulating IDO via blocked IL-10/IL-10RA signalling in MSCs. This advances IL-10RA interference in the tumour microenvironment (TME) to restore T cell cytotoxicity against cancers.
Competing Interests: Competing interests: The authors declare no competing interests. Ethics approval and consent to participate: The study was performed in accordance with the Declaration of Helsinki. The study was approved by the Research Ethics Committee, National Health Research Institutes (EC1111215-W, EC1111003-W and EC1100308-E). Informed consent forms were obtained from all participants.
(© 2024. The Author(s).)
Databáze: MEDLINE
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