L-Kynurenine participates in cancer immune evasion by downregulating hypoxic signaling in T lymphocytes
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 contrib...
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2023-12-01
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| Series: | OncoImmunology |
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| Online Access: | https://www.tandfonline.com/doi/10.1080/2162402X.2023.2244330 |
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| author | Stephanie Schlichtner Inna M. Yasinska Elena Klenova Maryam Abooali Gurprit S. Lall Steffen M. Berger Sabrina Ruggiero Dietmar Cholewa Milan Milošević Bernhard F. Gibbs Elizaveta Fasler-Kan Vadim V. Sumbayev |
| author_facet | Stephanie Schlichtner Inna M. Yasinska Elena Klenova Maryam Abooali Gurprit S. Lall Steffen M. Berger Sabrina Ruggiero Dietmar Cholewa Milan Milošević Bernhard F. Gibbs Elizaveta Fasler-Kan Vadim V. Sumbayev |
| author_sort | Stephanie Schlichtner |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-af8e958bbeec46739a4b45819fd24cbb |
| institution | DOAJ |
| issn | 2162-402X |
| language | English |
| publishDate | 2023-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | OncoImmunology |
| spelling | doaj-art-af8e958bbeec46739a4b45819fd24cbb2025-08-20T02:50:44ZengTaylor & Francis GroupOncoImmunology2162-402X2023-12-0112110.1080/2162402X.2023.2244330L-Kynurenine participates in cancer immune evasion by downregulating hypoxic signaling in T lymphocytesStephanie Schlichtner0Inna M. Yasinska1Elena Klenova2Maryam Abooali3Gurprit S. Lall4Steffen M. Berger5Sabrina Ruggiero6Dietmar Cholewa7Milan Milošević8Bernhard F. Gibbs9Elizaveta Fasler-Kan10Vadim V. Sumbayev11Medway School of Pharmacy, Universities of Kent and Greenwich, Chatham Maritime, UKMedway School of Pharmacy, Universities of Kent and Greenwich, Chatham Maritime, UKSchool of Biological Sciences, University of Essex, Colchester, UKMedway School of Pharmacy, Universities of Kent and Greenwich, Chatham Maritime, UKMedway School of Pharmacy, Universities of Kent and Greenwich, Chatham Maritime, UKDepartment of Pediatric Surgery, Children’s Hospital, Inselspital Bern, University of Bern and Department of Biomedical Research, University of Bern, Bern, SwitzerlandDepartment of Pediatric Surgery, Children’s Hospital, Inselspital Bern, University of Bern and Department of Biomedical Research, University of Bern, Bern, SwitzerlandDepartment of Pediatric Surgery, Children’s Hospital, Inselspital Bern, University of Bern and Department of Biomedical Research, University of Bern, Bern, SwitzerlandDepartment of Pediatric Surgery, Children’s Hospital, Inselspital Bern, University of Bern and Department of Biomedical Research, University of Bern, Bern, SwitzerlandMedway School of Pharmacy, Universities of Kent and Greenwich, Chatham Maritime, UKDepartment of Pediatric Surgery, Children’s Hospital, Inselspital Bern, University of Bern and Department of Biomedical Research, University of Bern, Bern, SwitzerlandMedway School of Pharmacy, Universities of Kent and Greenwich, Chatham Maritime, UKMalignant 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.https://www.tandfonline.com/doi/10.1080/2162402X.2023.2244330cancerimmune checkpointsimmune escapekynurenineT cells |
| spellingShingle | Stephanie Schlichtner Inna M. Yasinska Elena Klenova Maryam Abooali Gurprit S. Lall Steffen M. Berger Sabrina Ruggiero Dietmar Cholewa Milan Milošević Bernhard F. Gibbs Elizaveta Fasler-Kan Vadim V. Sumbayev L-Kynurenine participates in cancer immune evasion by downregulating hypoxic signaling in T lymphocytes OncoImmunology cancer immune checkpoints immune escape kynurenine T cells |
| title | L-Kynurenine participates in cancer immune evasion by downregulating hypoxic signaling in T lymphocytes |
| title_full | L-Kynurenine participates in cancer immune evasion by downregulating hypoxic signaling in T lymphocytes |
| title_fullStr | L-Kynurenine participates in cancer immune evasion by downregulating hypoxic signaling in T lymphocytes |
| title_full_unstemmed | L-Kynurenine participates in cancer immune evasion by downregulating hypoxic signaling in T lymphocytes |
| title_short | L-Kynurenine participates in cancer immune evasion by downregulating hypoxic signaling in T lymphocytes |
| title_sort | l kynurenine participates in cancer immune evasion by downregulating hypoxic signaling in t lymphocytes |
| topic | cancer immune checkpoints immune escape kynurenine T cells |
| url | https://www.tandfonline.com/doi/10.1080/2162402X.2023.2244330 |
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