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Tryptophan-derived microbial metabolites activate the aryl hydrocarbon receptor in tumor-associated macrophages to suppress anti-tumor immunity.
Hezaveh, Kebria; Shinde, Rahul S; Klötgen, Andreas; Halaby, Marie Jo; Lamorte, Sara; Ciudad, M Teresa; Quevedo, Rene; Neufeld, Luke; Liu, Zhe Qi; Jin, Robbie; Grünwald, Barbara T; Foerster, Elisabeth G; Chaharlangi, Danica; Guo, Mengdi; Makhijani, Priya; Zhang, Xin; Pugh, Trevor J; Pinto, Devanand M; Co, Ileana L; McGuigan, Alison P; Jang, Gun Ho; Khokha, Rama; Ohashi, Pamela S; O'Kane, Grainne M; Gallinger, Steven; Navarre, William W; Maughan, Heather; Philpott, Dana J; Brooks, David G; McGaha, Tracy L.
Afiliação
  • Hezaveh K; Tumor Immunotherapy Program, Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2M9, Canada.
  • Shinde RS; Tumor Immunotherapy Program, Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2M9, Canada.
  • Klötgen A; Department of Computational Biology of Infection Research, Helmholtz Centre for Infection Research, Braunschweig 38124, Germany.
  • Halaby MJ; Tumor Immunotherapy Program, Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2M9, Canada.
  • Lamorte S; Tumor Immunotherapy Program, Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2M9, Canada.
  • Ciudad MT; Tumor Immunotherapy Program, Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2M9, Canada.
  • Quevedo R; Tumor Immunotherapy Program, Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2M9, Canada.
  • Neufeld L; Tumor Immunotherapy Program, Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2M9, Canada; Department of Immunology, The University of Toronto, Toronto, ON M5S 1A8, Canada.
  • Liu ZQ; Tumor Immunotherapy Program, Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2M9, Canada; Department of Immunology, The University of Toronto, Toronto, ON M5S 1A8, Canada.
  • Jin R; Tumor Immunotherapy Program, Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2M9, Canada; Department of Immunology, The University of Toronto, Toronto, ON M5S 1A8, Canada.
  • Grünwald BT; Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada.
  • Foerster EG; Department of Immunology, The University of Toronto, Toronto, ON M5S 1A8, Canada.
  • Chaharlangi D; Department of Molecular Genetics, The University of Toronto, Toronto, ON M5S 1A8, Canada.
  • Guo M; Tumor Immunotherapy Program, Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2M9, Canada; Department of Immunology, The University of Toronto, Toronto, ON M5S 1A8, Canada.
  • Makhijani P; Tumor Immunotherapy Program, Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2M9, Canada; Department of Immunology, The University of Toronto, Toronto, ON M5S 1A8, Canada.
  • Zhang X; Tumor Immunotherapy Program, Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2M9, Canada.
  • Pugh TJ; Tumor Immunotherapy Program, Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2M9, Canada; Department of Medical Biophysics, The University of Toronto, Toronto, ON M5G 1L7, Canada; The Ontario Institute for Cancer Research, Toronto, ON M5G 0A3, Canada.
  • Pinto DM; National Research Council, Human Health Therapeutics, Halifax, NS B3H 3Z1, Canada.
  • Co IL; Institute of Biomedical Engineering, The University of Toronto, Toronto, ON M5S 3G9, Canada.
  • McGuigan AP; Institute of Biomedical Engineering, The University of Toronto, Toronto, ON M5S 3G9, Canada; Department of Chemical Engineering and Applied Chemistry, The University of Toronto, Toronto, ON M5S 3E5, Canada.
  • Jang GH; The Ontario Institute for Cancer Research, Toronto, ON M5G 0A3, Canada.
  • Khokha R; Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada; Department of Medical Biophysics, The University of Toronto, Toronto, ON M5G 1L7, Canada.
  • Ohashi PS; Tumor Immunotherapy Program, Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2M9, Canada; Department of Immunology, The University of Toronto, Toronto, ON M5S 1A8, Canada.
  • O'Kane GM; The Ontario Institute for Cancer Research, Toronto, ON M5G 0A3, Canada; Division of Medical Oncology, Department of Medicine, The University of Toronto, Toronto, ON M5S 3H2, Canada.
  • Gallinger S; The Ontario Institute for Cancer Research, Toronto, ON M5G 0A3, Canada; Department of Laboratory Medicine and Pathobiology, The University of Toronto, Toronto, ON M5S 1A8, Canada; Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada.
  • Navarre WW; Department of Molecular Genetics, The University of Toronto, Toronto, ON M5S 1A8, Canada.
  • Maughan H; Ronin Institute, Montclair, NJ 07043, USA.
  • Philpott DJ; Department of Immunology, The University of Toronto, Toronto, ON M5S 1A8, Canada.
  • Brooks DG; Tumor Immunotherapy Program, Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2M9, Canada; Department of Immunology, The University of Toronto, Toronto, ON M5S 1A8, Canada.
  • McGaha TL; Tumor Immunotherapy Program, Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2M9, Canada; Department of Immunology, The University of Toronto, Toronto, ON M5S 1A8, Canada. Electronic address: tmcgaha@uhnresearch.ca.
Immunity ; 55(2): 324-340.e8, 2022 02 08.
Article em En | MEDLINE | ID: mdl-35139353
ABSTRACT
The aryl hydrocarbon receptor (AhR) is a sensor of products of tryptophan metabolism and a potent modulator of immunity. Here, we examined the impact of AhR in tumor-associated macrophage (TAM) function in pancreatic ductal adenocarcinoma (PDAC). TAMs exhibited high AhR activity and Ahr-deficient macrophages developed an inflammatory phenotype. Deletion of Ahr in myeloid cells or pharmacologic inhibition of AhR reduced PDAC growth, improved efficacy of immune checkpoint blockade, and increased intra-tumoral frequencies of IFNγ+CD8+ T cells. Macrophage tryptophan metabolism was not required for this effect. Rather, macrophage AhR activity was dependent on Lactobacillus metabolization of dietary tryptophan to indoles. Removal of dietary tryptophan reduced TAM AhR activity and promoted intra-tumoral accumulation of TNFα+IFNγ+CD8+ T cells; provision of dietary indoles blocked this effect. In patients with PDAC, high AHR expression associated with rapid disease progression and mortality, as well as with an immune-suppressive TAM phenotype, suggesting conservation of this regulatory axis in human disease.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Triptofano / Receptores de Hidrocarboneto Arílico / Macrófagos Associados a Tumor / Tolerância Imunológica Tipo de estudo: Prognostic_studies / Risk_factors_studies Limite: Animals / Humans Idioma: En Revista: Immunity Assunto da revista: ALERGIA E IMUNOLOGIA Ano de publicação: 2022 Tipo de documento: Article País de afiliação: Canadá
Texto completo
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Triptofano / Receptores de Hidrocarboneto Arílico / Macrófagos Associados a Tumor / Tolerância Imunológica Tipo de estudo: Prognostic_studies / Risk_factors_studies Limite: Animals / Humans Idioma: En Revista: Immunity Assunto da revista: ALERGIA E IMUNOLOGIA Ano de publicação: 2022 Tipo de documento: Article País de afiliação: Canadá