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

ABSTRACT

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.

KEYWORDS:

• cancer
• immune checkpoints
• immune escape
• kynurenine
• T cells

Acknowledgments

We thank Diamond Light Source for access to the B23 beamline and funding projects SM24509, SM20755, and SM21202. This work was also supported by the British Society for Immunology (to SS) and Swiss Batzebär grant (to EF-K and SB).

Disclosure statement

No potential conflict of interest was reported by the authors.

Data availability statement

The data presented in this study are presented in the main and supplementary figures . All the raw data are available from the corresponding author upon request.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/2162402X.2023.2244330.

Additional information

Funding

The work was supported by the British Society for Immunology, Diamond Light Source Ltd and Swiss Batzebär grant.