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Journal Article Epublish 3 citations

PubMed: 38789421 DOI: 10.1038/s41467-024-48653-y

Deleting the mitochondrial respiration negative regulator MCJ enhances the efficacy of CD8 T cell adoptive therapies in pre-clinical studies.

Nat Commun 15(1):4444

Authors: Meng-Han Wu, Felipe Valenca-Pereira, Francesca Cendali, Emily L Giddings, Catherine Pham-Danis, Michael C Yarnell, Amanda J Novak, Tonya M Brunetti, Scott B Thompson, Jorge Henao-Mejia, Richard A Flavell, Angelo D'Alessandro, M Eric Kohler, Mercedes Rincon

Affiliations

  • Department of Immunology and Microbiology, University of Colorado, Anschutz Medical Campus, Aurora, CO, USA.
  • Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
  • Division of Immunobiology, Department of Medicine, Larner College of Medicine, University of Vermont, Burlington, VT, USA.
  • Department of Pediatric Hematology, Oncology and Bone Marrow Transplant, University of Colorado, Anschutz Medical Campus, Aurora, CO, USA.
  • Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • Division of Transplant Immunology, Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA, USA.
  • Department of Immunobiology, School of Medicine, Yale University, New Haven, CT, USA.
  • Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT, USA.
  • Department of Pediatric Hematology, Oncology and Bone Marrow Transplant, University of Colorado, Anschutz Medical Campus, Aurora, CO, USA.
  • Center for Cancer and Blood Disorders, Children's Hospital Colorado, Aurora, CO, USA.
  • Department of Immunology and Microbiology, University of Colorado, Anschutz Medical Campus, Aurora, CO, USA.
  • Division of Immunobiology, Department of Medicine, Larner College of Medicine, University of Vermont, Burlington, VT, USA.

Abstract

Mitochondrial respiration is essential for the survival and function of T cells used in adoptive cellular therapies. However, strategies that specifically enhance mitochondrial respiration to promote T cell function remain limited. Here, we investigate methylation-controlled J protein (MCJ), an endogenous negative regulator of mitochondrial complex I expressed in CD8 cells, as a target for improving the efficacy of adoptive T cell therapies. We demonstrate that MCJ inhibits mitochondrial respiration in murine CD8 CAR-T cells and that deletion of MCJ increases their in vitro and in vivo efficacy against murine B cell leukaemia. Similarly, MCJ deletion in ovalbumin (OVA)-specific CD8 T cells also increases their efficacy against established OVA-expressing melanoma tumors in vivo. Furthermore, we show for the first time that MCJ is expressed in human CD8 cells and that the level of MCJ expression correlates with the functional activity of CD8 CAR-T cells. Silencing MCJ expression in human CD8 CAR-T cells increases their mitochondrial metabolism and enhances their anti-tumor activity. Thus, targeting MCJ may represent a potential therapeutic strategy to increase mitochondrial metabolism and improve the efficacy of adoptive T cell therapies.

MeSH

Biological Science Disciplines, Respiration, Cells, Therapeutics, Neoplasms, T-Lymphocytes, B-Lymphocytes

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