L-Kynurenine participates in cancer immune evasion by downregulating hypoxic signaling in T lymphocytes.

Schlichtner, Stephanie; Yasinska, Inna M; Klenova, Elena; Abooali, Maryam; Lall, Gurprit S; Berger, Steffen M; Ruggiero, Sabrina; Cholewa, Dietmar; Milošević, Milan; Gibbs, Bernhard F; Fasler-Kan, Elizaveta; Sumbayev, Vadim V (2023). L-Kynurenine participates in cancer immune evasion by downregulating hypoxic signaling in T lymphocytes. Oncoimmunology, 12(1), p. 2244330. Taylor & Francis 10.1080/2162402X.2023.2244330

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Malignant 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.

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