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

  • Br J Cancer. 2025 Jan;132(1):126-136. doi: 10.1038/s41416-024-02893-3.
Tzong-Shyuan Tai  #  1 ,  Duen-Wei Hsu  #  2 ,  Yu-Shao Yang  #  3  4 ,  Ching-Yen Tsai  5 ,  Jai-Wen Shi  2  3 ,  Chien-Hui Wu  6 ,  Shu-Ching Hsu  7  8  9  10  11
Affiliations
  • 1. Department of Medical Research and Development, Chang Gung Memorial Hospital, Taoyuan, Taiwan.
  • 2. Department of Biotechnology, National Kaohsiung Normal University, Kaohsiung City, Taiwan.
  • 3. National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Miaoli, Taiwan.
  • 4. Institute of Bioinformatics and Structural Biology, National Tsing Hua University, Hsinchu, Taiwan.
  • 5. Transgenic Core Facility, Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan.
  • 6. Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan.
  • 7. National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Miaoli, Taiwan. [email protected].
  • 8. Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung City, Taiwan. [email protected].
  • 9. Graduate Institute of Biomedical Science, Immunology Research and Development Center, China Medical University, Taichung City, Taiwan. [email protected].
  • 10. Department of Biomedical Sciences and Engineering, Tzu Chi University, Hualien, Taiwan. [email protected].
  • 11. Doctoral Program in Tissue Engineering and Regenerative Medicine, National Chung Hsing University, Taichung City, Taiwan. [email protected].
  • # Contributed equally.
PMID: 39592739 DOI: 10.1038/s41416-024-02893-3
Abstract

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.

Products