Blockade of the AHR restricts a Treg-macrophage suppressive axis induced by L-Kynurenine

Luis Felipe Campesato ¹, Sadna Budhu ¹, Jeremy Tchaicha ², Chien-Huan Weng ¹, Mathieu Gigoux ¹, Ivan Jose Cohen ³, David Redmond ¹, Levi Mangarin ¹, Stephane Pourpe ¹, Cailian Liu ¹, Roberta Zappasodi ¹, Dmitriy Zamarin ¹, Jill Cavanaugh ², Alfredo C Castro ², Mark G Manfredi ², Karen McGovern ², Taha Merghoub ⁴, Jedd D Wolchok ⁵

Affiliations

¹ Swim Across America and Ludwig Collaborative Laboratory, Immunology Program, Parker Institute for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
² Ikena Oncology, Boston, MA, USA.
³ Department of Neurology and Louis V. Gerstner Jr Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
⁴ Swim Across America and Ludwig Collaborative Laboratory, Immunology Program, Parker Institute for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, NY, USA. merghout@mskcc.org.
⁵ Swim Across America and Ludwig Collaborative Laboratory, Immunology Program, Parker Institute for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, NY, USA. wolchokj@mskcc.org.

PMID: 32782249
53 References
41 citations

Abstract

Tryptophan catabolism by the enzymes indoleamine 2,3-dioxygenase 1 and tryptophan 2,3-dioxygenase 2 (IDO/TDO) promotes immunosuppression across different cancer types. The tryptophan metabolite L-Kynurenine (Kyn) interacts with the ligand-activated transcription factor aryl hydrocarbon receptor (AHR) to drive the generation of Tregs and tolerogenic myeloid cells and PD-1 up-regulation in CD8+ T cells. Here, we show that the AHR pathway is selectively active in IDO/TDO-overexpressing tumors and is associated with resistance to immune checkpoint inhibitors. We demonstrate that IDO-Kyn-AHR-mediated immunosuppression depends on an interplay between Tregs and tumor-associated macrophages, which can be reversed by AHR inhibition. Selective AHR blockade delays progression in IDO/TDO-overexpressing tumors, and its efficacy is improved in combination with PD-1 blockade. Our findings suggest that blocking the AHR pathway in IDO/TDO expressing tumors would overcome the limitation of single IDO or TDO targeting agents and constitutes a personalized approach to immunotherapy, particularly in combination with immune checkpoint inhibitors.

Other Links

Free PMC article
Full text on Nature communications

Cited By

Citedby
Metabolic Cancer-Macrophage Crosstalk in the Tumor Microenvironment. Kyra E de Goede, Amber J M Driessen, Jan Van den Bossche. Biology (Basel), 2020 Nov 12; 9(11). PMID: 33171762 Free PMC article. Review.
How Ah Receptor Ligand Specificity Became Important in Understanding Its Physiological Function. Iain A Murray, Gary H Perdew. Int J Mol Sci, 2020 Dec 23; 21(24). PMID: 33348604 Free PMC article. Review.
Cancer Cells Resistance Shaping by Tumor Infiltrating Myeloid Cells. Marcin Domagala, Chloé Laplagne, +4 authors, Mary Poupot. less Cancers (Basel), 2021 Jan 10; 13(2). PMID: 33418996 Free PMC article. Review.
AhR and Cancer: From Gene Profiling to Targeted Therapy. Anaïs Paris, Nina Tardif, Marie-Dominique Galibert, Sébastien Corre. Int J Mol Sci, 2021 Jan 17; 22(2). PMID: 33451095 Free PMC article. Review.
Metabolic profiles of regulatory T cells in the tumour microenvironment. Disha Rao, Fabienne Verburg, +3 authors, Christian U Blank. less Cancer Immunol Immunother, 2021 Feb 13; 70(9). PMID: 33576875 Review.
Tryptophan: A Rheostat of Cancer Immune Escape Mediated by Immunosuppressive Enzymes IDO1 and TDO. Minah Kim, Petr Tomek. Front Immunol, 2021 Mar 13; 12. PMID: 33708223 Free PMC article. Review.
Targeting the Aryl Hydrocarbon Receptor Signaling Pathway in Breast Cancer Development. Christoph F A Vogel, Gwendal Lazennec, +12 authors, Colleen Sweeney. less Front Immunol, 2021 Mar 26; 12. PMID: 33763068 Free PMC article.
CRISPR screens identify tumor-promoting genes conferring melanoma cell plasticity and resistance. Arthur Gautron, Laura Bachelot, +12 authors, David Gilot. less EMBO Mol Med, 2021 Mar 17; 13(5). PMID: 33724679 Free PMC article.
Tryptophan Metabolites at the Crossroad of Immune-Cell Interaction via the Aryl Hydrocarbon Receptor: Implications for Tumor Immunotherapy. Marco Gargaro, Giorgia Manni, +2 authors, Giulia Scalisi, Paolo Puccetti, Francesca Fallarino. less Int J Mol Sci, 2021 May 01; 22(9). PMID: 33924971 Free PMC article. Review.
Recent advances in the development of AHR antagonists in immuno-oncology. Lijun Sun. RSC Med Chem, 2021 Jul 06; 12(6). PMID: 34223158 Free PMC article. Review.
Kynurenines as a Novel Target for the Treatment of Malignancies. Adrian Mor, Anna Tankiewicz-Kwedlo, Dariusz Pawlak. Pharmaceuticals (Basel), 2021 Jul 03; 14(7). PMID: 34201791 Free PMC article. Review.
Role of Kynurenine Pathway in Oxidative Stress during Neurodegenerative Disorders. Adrian Mor, Anna Tankiewicz-Kwedlo, Anna Krupa, Dariusz Pawlak. Cells, 2021 Jul 03; 10(7). PMID: 34206739 Free PMC article. Review.
Macrophages, as a Promising Strategy to Targeted Treatment for Colorectal Cancer Metastasis in Tumor Immune Microenvironment. Yingru Zhang, Yiyang Zhao, Qi Li, Yan Wang. Front Immunol, 2021 Jul 31; 12. PMID: 34326840 Free PMC article. Review.
IFNγ signaling integrity in colorectal cancer immunity and immunotherapy. Wan Du, Timothy L Frankel, Michael Green, Weiping Zou. Cell Mol Immunol, 2021 Aug 14; 19(1). PMID: 34385592 Free PMC article. Review.
Tryptophan metabolism in brain tumors - IDO and beyond. Michael Platten, Mirco Friedrich, +2 authors, Derek A Wainwright, Verena Panitz, Christiane A Opitz. less Curr Opin Immunol, 2021 Apr 05; 70. PMID: 33813026 Free PMC article. Review.
The Crucial Roles of Intermediate Metabolites in Cancer. Sisi Huang, Zhiqin Wang, Liang Zhao. Cancer Manag Res, 2021 Aug 20; 13. PMID: 34408491 Free PMC article. Review.
Mechanisms of regulatory T cell infiltration in tumors: implications for innovative immune precision therapies. Hiroyoshi Nishikawa, Shohei Koyama. J Immunother Cancer, 2021 Aug 01; 9(7). PMID: 34330764 Free PMC article. Review.
Immunosuppressive network promotes immunosenescence associated with aging and chronic inflammatory conditions. Antero Salminen. J Mol Med (Berl), 2021 Aug 26; 99(11). PMID: 34432073 Free PMC article. Review.
Kynurenine Monooxygenase Expression and Activity in Human Astrocytomas. Gustavo Ignacio Vázquez Cervantes, Benjamín Pineda, +7 authors, Verónica Pérez de la Cruz. less Cells, 2021 Aug 28; 10(8). PMID: 34440798 Free PMC article.
Amino Acid Transport and Metabolism in Myeloid Function. Marie Jo Halaby, Tracy L McGaha. Front Immunol, 2021 Aug 31; 12. PMID: 34456909 Free PMC article. Review.
Blockade of IDO-Kynurenine-AhR Axis Ameliorated Colitis-Associated Colon Cancer via Inhibiting Immune Tolerance. Xin Zhang, Xiuting Liu, +4 authors, Rong Hu. less Cell Mol Gastroenterol Hepatol, 2021 Jun 05; 12(4). PMID: 34087454 Free PMC article.
Aryl hydrocarbon receptor (AHR) functions in infectious and sterile inflammation and NAD+-dependent metabolic adaptation. Karl Walter Bock. Arch Toxicol, 2021 Sep 25; 95(11). PMID: 34559251 Free PMC article. Review.
The Tumor Microenvironment-Dependent Transcription Factors AHR and HIF-1α Are Dispensable for Leukemogenesis in the Eµ-TCL1 Mouse Model of Chronic Lymphocytic Leukemia. Susanne Gonder, Anne Largeot, +5 authors, Etienne Moussay. less Cancers (Basel), 2021 Sep 29; 13(18). PMID: 34572746 Free PMC article.
Constitutive TDO2 expression promotes liver cancer progression by an autocrine IL-6 signaling pathway. Zhengzhong Wu, Leye Yan, +2 authors, Junqing Lin, Kun Ke, Weizhu Yang. less Cancer Cell Int, 2021 Oct 19; 21(1). PMID: 34657635 Free PMC article.
IDO in Colorectal Tumorigenesis: Involvement of Immune Tolerance and Significance in Prevention and Therapy. Shunan Tang, Jingya Wang, Siwang Yu. Cell Mol Gastroenterol Hepatol, 2021 Jul 20; 12(4). PMID: 34280382 Free PMC article.
Metabolic regulation of the cancer-immunity cycle. Luis F Somarribas Patterson, Santosha A Vardhana. Trends Immunol, 2021 Oct 07; 42(11). PMID: 34610889 Free PMC article. Review.
Immunosuppressive metabolites in tumoral immune evasion: redundancies, clinical efforts, and pathways forward. Maria Rain Jennings, David Munn, John Blazeck. J Immunother Cancer, 2021 Oct 21; 9(10). PMID: 34667078 Free PMC article. Review.
Pharmacological blockage of the AHR-CYP1A1 axis: a call for in vivo evidence. N R Coelho, A B Pimpão, +4 authors, S A Pereira. less J Mol Med (Berl), 2021 Nov 21; 100(2). PMID: 34800164 Free PMC article. Review.
The Metabolic Control of Myeloid Cells in the Tumor Microenvironment. Eloise Ramel, Sebastian Lillo, +3 authors, Maya Saleh. less Cells, 2021 Nov 28; 10(11). PMID: 34831183 Free PMC article. Review.
Deep learning model enables the discovery of a novel immunotherapeutic agent regulating the kynurenine pathway. Jeong Hun Kim, Won Suk Lee, +10 authors, Chan Kim. less Oncoimmunology, 2021 Dec 04; 10(1). PMID: 34858729 Free PMC article.
Metabolism of tissue macrophages in homeostasis and pathology. Stefanie K Wculek, Gillian Dunphy, +2 authors, David Sancho. less Cell Mol Immunol, 2021 Dec 09; 19(3). PMID: 34876704 Free PMC article. Review.
Immunologically modified enzyme-responsive micelles regulate the tumor microenvironment for cancer immunotherapy. Zhimin Han, Chunai Gong, +5 authors, Zongguang Tai. less Mater Today Bio, 2021 Dec 24; 13. PMID: 34938989 Free PMC article.
Barriers to Immunotherapy in Ovarian Cancer: Metabolic, Genomic, and Immune Perturbations in the Tumour Microenvironment. Racheal Louise Johnson, Michele Cummings, +3 authors, Nicolas Michel Orsi. less Cancers (Basel), 2021 Dec 25; 13(24). PMID: 34944851 Free PMC article. Review.
The past, present, and future of enzyme-based therapies. Jennifer N Hennigan, Michael D Lynch. Drug Discov Today, 2021 Sep 20; 27(1). PMID: 34537332 Free PMC article. Review.
Indoleamine 2,3-Dioxygenase 1: A Promising Therapeutic Target in Malignant Tumor. Xiaotian Song, Qianqian Si, +5 authors, Zhiyan Yao. less Front Immunol, 2022 Jan 11; 12. PMID: 35003126 Free PMC article. Review.
Influence of the Metabolism on Myeloid Cell Functions in Cancers: Clinical Perspectives. Thomas Boyer, Céline Blaye, Nicolas Larmonier, Charlotte Domblides. Cells, 2022 Feb 16; 11(3). PMID: 35159363 Free PMC article. Review.
Cell-intrinsic view of the aryl hydrocarbon receptor in tumor immunity. Joseph W Dean, Liang Zhou. Trends Immunol, 2022 Feb 09; 43(3). PMID: 35131180 Free PMC article. Review.
An imbalance of the IL-33/ST2-AXL-efferocytosis axis induces pregnancy loss through metabolic reprogramming of decidual macrophages. Yan-Ran Sheng, Wen-Ting Hu, +5 authors, Xiao-Yong Zhu. less Cell Mol Life Sci, 2022 Mar 05; 79(3). PMID: 35244789
Tryptophan Metabolism and COVID-19-Induced Skeletal Muscle Damage: Is ACE2 a Key Regulator? Hikari Takeshita, Koichi Yamamoto. Front Nutr, 2022 Apr 26; 9. PMID: 35463998 Free PMC article. Review.
Comparative metabolomics analysis of bronchial epithelium during barrier establishment after allergen exposure. Juan Carlos López-Rodríguez, Juan Rodríguez-Coira, +6 authors, Eva Batanero. less Clin Transl Allergy, 2021 Sep 29; 11(7). PMID: 34582104 Free PMC article.
Myeloid cell-targeted therapies for solid tumours. Sangeeta Goswami, Swetha Anandhan, Deblina Raychaudhuri, Padmanee Sharma. Nat Rev Immunol, 2022 Jun 14;. PMID: 35697799 Review.

BioKDE: Biomedical Knowledge Discovery Engine

Abstract

Other Links