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L-Kynurenine participates in cancer immune evasion by downregulating hypoxic signaling in T lymphocytes
- Source :
- OncoImmunology, Vol 12, Iss 1 (2023)
- Publication Year :
- 2023
- Publisher :
- Taylor & Francis Group, 2023.
-
Abstract
- ABSTRACTMalignant tumors often escape anticancer immune surveillance by suppressing the cytotoxic functions of T lymphocytes. While many of these immune evasion networks include checkpoint proteins, small molecular weight compounds, such as the amino acid L-kynurenine (LKU), could also substantially contribute to the suppression of anti-cancer immunity. However, the biochemical mechanisms underlying the suppressive effects of LKU on T-cells remain unclear. Here, we report for the first time that LKU suppresses T cell function as an aryl hydrocarbon receptor (AhR) ligand. The presence of LKU in T cells is associated with AhR activation, which results in competition between AhR and hypoxia-inducible factor 1 alpha (HIF-1α) for the AhR nuclear translocator, ARNT, leading to T cell exhaustion. The expression of indoleamine 2,3-dioxygenase 1 (IDO1, the enzyme that leads to LKU generation) is induced by the TGF-β-Smad-3 pathway. We also show that IDO-negative cancers utilize an alternative route for LKU production via the endogenous inflammatory mediator, the high mobility group box 1 (HMGB-1)-interferon-gamma (IFN-γ) axis. In addition, other IDO-negative tumors (like T-cell lymphomas) trigger IDO1 activation in eosinophils present in the tumor microenvironment (TME). These mechanisms suppress cytotoxic T cell function, and thus support the tumor immune evasion machinery.
Details
- Language :
- English
- ISSN :
- 2162402X
- Volume :
- 12
- Issue :
- 1
- Database :
- Directory of Open Access Journals
- Journal :
- OncoImmunology
- Publication Type :
- Academic Journal
- Accession number :
- edsdoj.f8e958bbeec46739a4b45819fd24cbb
- Document Type :
- article
- Full Text :
- https://doi.org/10.1080/2162402X.2023.2244330