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Microenvironmental ammonia enhances T cell exhaustion in colorectal cancer.
Bell, Hannah N; Huber, Amanda K; Singhal, Rashi; Korimerla, Navyateja; Rebernick, Ryan J; Kumar, Roshan; El-Derany, Marwa O; Sajjakulnukit, Peter; Das, Nupur K; Kerk, Samuel A; Solanki, Sumeet; James, Jadyn G; Kim, Donghwan; Zhang, Li; Chen, Brandon; Mehra, Rohit; Frankel, Timothy L; Gyorffy, Balázs; Fearon, Eric R; Pasca di Magliano, Marina; Gonzalez, Frank J; Banerjee, Ruma; Wahl, Daniel R; Lyssiotis, Costas A; Green, Michael; Shah, Yatrik M.
Afiliación
  • Bell HN; Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA.
  • Huber AK; Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, USA.
  • Singhal R; Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA.
  • Korimerla N; Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, USA; University of Michigan Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA.
  • Rebernick RJ; Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA.
  • Kumar R; Department of Biological Chemistry, University of Michigan Medical School, Ann Arbor, MI, USA.
  • El-Derany MO; Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Biochemistry, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt.
  • Sajjakulnukit P; Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA.
  • Das NK; Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA.
  • Kerk SA; Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA.
  • Solanki S; Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA.
  • James JG; Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, USA.
  • Kim D; Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
  • Zhang L; Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA.
  • Chen B; Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA.
  • Mehra R; Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
  • Frankel TL; Department of Surgery, University of Michigan, Ann Arbor, MI, USA; Department of Human Genetics, University of Michigan, Ann Arbor, MI, USA.
  • Gyorffy B; Department of Bioinformatics and 2(nd) Department of Pediatrics, Semmelweis University, Budapest, Hungary; TTK Cancer Biomarker Research Group, Institute of Enzymology, Budapest, Hungary.
  • Fearon ER; University of Michigan Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA; Department of Pathology, University of Michigan, Ann Arbor, MI, USA; Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA; Department of Human Genetics, University of Michigan, Ann Arbor, M
  • Pasca di Magliano M; Department of Surgery, University of Michigan, Ann Arbor, MI, USA; Department of Human Genetics, University of Michigan, Ann Arbor, MI, USA.
  • Gonzalez FJ; Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
  • Banerjee R; Department of Biological Chemistry, University of Michigan Medical School, Ann Arbor, MI, USA.
  • Wahl DR; Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, USA; University of Michigan Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA.
  • Lyssiotis CA; Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA; University of Michigan Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA; Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
  • Green M; Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, USA; University of Michigan Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA; Veteran's Affairs Ann Arbor Healthcare System, Ann Arbor, MI, USA.
  • Shah YM; Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA; University of Michigan Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA; Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA. Electronic address: shahy@umich.e
Cell Metab ; 35(1): 134-149.e6, 2023 01 03.
Article en En | MEDLINE | ID: mdl-36528023
ABSTRACT
Effective therapies are lacking for patients with advanced colorectal cancer (CRC). The CRC tumor microenvironment has elevated metabolic waste products due to altered metabolism and proximity to the microbiota. The role of metabolite waste in tumor development, progression, and treatment resistance is unclear. We generated an autochthonous metastatic mouse model of CRC and used unbiased multi-omic analyses to reveal a robust accumulation of tumoral ammonia. The high ammonia levels induce T cell metabolic reprogramming, increase exhaustion, and decrease proliferation. CRC patients have increased serum ammonia, and the ammonia-related gene signature correlates with altered T cell response, adverse patient outcomes, and lack of response to immune checkpoint blockade. We demonstrate that enhancing ammonia clearance reactivates T cells, decreases tumor growth, and extends survival. Moreover, decreasing tumor-associated ammonia enhances anti-PD-L1 efficacy. These findings indicate that enhancing ammonia detoxification can reactivate T cells, highlighting a new approach to enhance the efficacy of immunotherapies.
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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Neoplasias Colorrectales / Amoníaco Tipo de estudio: Prognostic_studies Límite: Animals Idioma: En Revista: Cell Metab Asunto de la revista: METABOLISMO Año: 2023 Tipo del documento: Article País de afiliación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Neoplasias Colorrectales / Amoníaco Tipo de estudio: Prognostic_studies Límite: Animals Idioma: En Revista: Cell Metab Asunto de la revista: METABOLISMO Año: 2023 Tipo del documento: Article País de afiliación: Estados Unidos