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The cytokine Meteorin-like inhibits anti-tumor CD8+ T cell responses by disrupting mitochondrial function.
Jackson, Christopher M; Pant, Ayush; Dinalankara, Wikum; Choi, John; Jain, Aanchal; Nitta, Ryan; Yazigi, Eli; Saleh, Laura; Zhao, Liang; Nirschl, Thomas R; Kochel, Christina M; Hwa-Lin Bergsneider, Brandon; Routkevitch, Denis; Patel, Kisha; Cho, Kwang Bog; Tzeng, Stephany; Neshat, Sarah Y; Kim, Young-Hoon; Smith, Barbara J; Ramello, Maria Cecilia; Sotillo, Elena; Wang, Xinnan; Green, Jordan J; Bettegowda, Chetan; Li, Gordon; Brem, Henry; Mackall, Crystal L; Pardoll, Drew M; Drake, Charles G; Marchionni, Luigi; Lim, Michael.
  • Jackson CM; Department of Neurosurgery, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. Electronic address: cjacks53@jhmi.edu.
  • Pant A; Bloomberg-Kimmel Institute for Immunotherapy, Departments of Oncology and Medicine, and the Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Dinalankara W; Bloomberg-Kimmel Institute for Immunotherapy, Departments of Oncology and Medicine, and the Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Choi J; Department of Neurosurgery, Stanford School of Medicine, Palo Alto, CA, USA.
  • Jain A; Department of Neurosurgery, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Nitta R; Department of Neurosurgery, Stanford School of Medicine, Palo Alto, CA, USA.
  • Yazigi E; Department of Neurosurgery, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Saleh L; Department of Neurosurgery, Stanford School of Medicine, Palo Alto, CA, USA.
  • Zhao L; Bloomberg-Kimmel Institute for Immunotherapy, Departments of Oncology and Medicine, and the Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Nirschl TR; Bloomberg-Kimmel Institute for Immunotherapy, Departments of Oncology and Medicine, and the Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Kochel CM; Bloomberg-Kimmel Institute for Immunotherapy, Departments of Oncology and Medicine, and the Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Hwa-Lin Bergsneider B; Department of Neurosurgery, Stanford School of Medicine, Palo Alto, CA, USA.
  • Routkevitch D; Department of Neurosurgery, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Patel K; Department of Neurosurgery, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Cho KB; Department of Neurosurgery, Stanford School of Medicine, Palo Alto, CA, USA.
  • Tzeng S; Biomedical Engineering Department, Johns Hopkins University, Baltimore, MD, USA.
  • Neshat SY; Biomedical Engineering Department, Johns Hopkins University, Baltimore, MD, USA.
  • Kim YH; Department of Neurosurgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.
  • Smith BJ; Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Ramello MC; Center for Cell Therapy, Stanford Cancer Institute, Stanford School of Medicine, Stanford, CA, USA.
  • Sotillo E; Center for Cell Therapy, Stanford Cancer Institute, Stanford School of Medicine, Stanford, CA, USA.
  • Wang X; Department of Neurosurgery, Stanford School of Medicine, Palo Alto, CA, USA.
  • Green JJ; Biomedical Engineering Department, Johns Hopkins University, Baltimore, MD, USA.
  • Bettegowda C; Department of Neurosurgery, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Li G; Department of Neurosurgery, Stanford School of Medicine, Palo Alto, CA, USA.
  • Brem H; Department of Neurosurgery, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Mackall CL; Center for Cell Therapy, Stanford Cancer Institute, Stanford School of Medicine, Stanford, CA, USA; Department of Pediatrics, Stanford School of Medicine, Stanford, CA, USA; Department of Medicine, Stanford School of Medicine, Stanford, CA, USA.
  • Pardoll DM; Bloomberg-Kimmel Institute for Immunotherapy, Departments of Oncology and Medicine, and the Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Drake CG; Bloomberg-Kimmel Institute for Immunotherapy, Departments of Oncology and Medicine, and the Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Marchionni L; Bloomberg-Kimmel Institute for Immunotherapy, Departments of Oncology and Medicine, and the Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Lim M; Department of Neurosurgery, Stanford School of Medicine, Palo Alto, CA, USA. Electronic address: mklim@stanford.edu.
Immunity ; 57(8): 1864-1877.e9, 2024 Aug 13.
Article en En | MEDLINE | ID: mdl-39111315
ABSTRACT
Tumor-infiltrating lymphocyte (TIL) hypofunction contributes to the progression of advanced cancers and is a frequent target of immunotherapy. Emerging evidence indicates that metabolic insufficiency drives T cell hypofunction during tonic stimulation, but the signals that initiate metabolic reprogramming in this context are largely unknown. Here, we found that Meteorin-like (METRNL), a metabolically active cytokine secreted by immune cells in the tumor microenvironment (TME), induced bioenergetic failure of CD8+ T cells. METRNL was secreted by CD8+ T cells during repeated stimulation and acted via both autocrine and paracrine signaling. Mechanistically, METRNL increased E2F-peroxisome proliferator-activated receptor delta (PPARδ) activity, causing mitochondrial depolarization and decreased oxidative phosphorylation, which triggered a compensatory bioenergetic shift to glycolysis. Metrnl ablation or downregulation improved the metabolic fitness of CD8+ T cells and enhanced tumor control in several tumor models, demonstrating the translational potential of targeting the METRNL-E2F-PPARδ pathway to support bioenergetic fitness of CD8+ TILs.
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Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Linfocitos Infiltrantes de Tumor / Linfocitos T CD8-positivos / Microambiente Tumoral / Mitocondrias Límite: Animals / Humans Idioma: En Año: 2024 Tipo del documento: Article
Texto completo
Imprimir
XML
PubMed Links
Search on Google

Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Linfocitos Infiltrantes de Tumor / Linfocitos T CD8-positivos / Microambiente Tumoral / Mitocondrias Límite: Animals / Humans Idioma: En Año: 2024 Tipo del documento: Article