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

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 () and Mercedes Rincon ()
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Meng-Han Wu: University of Colorado, Anschutz Medical Campus
Felipe Valenca-Pereira: University of Colorado, Anschutz Medical Campus
Francesca Cendali: University of Colorado Anschutz Medical Campus
Emily L. Giddings: Larner College of Medicine, University of Vermont
Catherine Pham-Danis: Oncology and Bone Marrow Transplant, University of Colorado, Anschutz Medical Campus
Michael C. Yarnell: Oncology and Bone Marrow Transplant, University of Colorado, Anschutz Medical Campus
Amanda J. Novak: Oncology and Bone Marrow Transplant, University of Colorado, Anschutz Medical Campus
Tonya M. Brunetti: University of Colorado, Anschutz Medical Campus
Scott B. Thompson: University of Colorado, Anschutz Medical Campus
Jorge Henao-Mejia: University of Pennsylvania
Richard A. Flavell: School of Medicine, Yale University
Angelo D’Alessandro: University of Colorado Anschutz Medical Campus
M. Eric Kohler: Oncology and Bone Marrow Transplant, University of Colorado, Anschutz Medical Campus
Mercedes Rincon: University of Colorado, Anschutz Medical Campus

Nature Communications, 2024, vol. 15, issue 1, 1-22

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-48653-y

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