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

• Published in: Nature communications 2024-05, Vol.15 (1), p.4444-22, Article 4444
• Main Authors: Wu, Meng-Han, Valenca-Pereira, Felipe, Cendali, Francesca, Giddings, Emily L., Pham-Danis, Catherine, Yarnell, Michael C., Novak, Amanda J., Brunetti, Tonya M., Thompson, Scott B., Henao-Mejia, Jorge, Flavell, Richard A., D’Alessandro, Angelo, Kohler, M. Eric, Rincon, Mercedes
• Format: Article
• Language: English
• Subjects: 13/1; 13/106; 13/109; 13/21; 13/31; 13/51; 13/89; 14; 38/91; 49/88; 49/90; 631/250/251; 631/67/1059/2325; 631/67/1813/1634; 631/67/2327; 631/67/2332; 64/60; 82/58; 96/34; 96/35; 96/63; Animals; Antitumor agents; CD8 antigen; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - metabolism; Cell Line, Tumor; Cell Respiration; Cell therapy; Chimeric antigen receptors; Clonal deletion; Deletion; Down-regulation; Effectiveness; Electron transport chain; Female; Humanities and Social Sciences; Humans; Immunotherapy, Adoptive - methods; J protein; Leukemia; Lymphocytes; Lymphocytes T; Melanoma; Melanoma, Experimental - immunology; Melanoma, Experimental - therapy; Metabolism; Methylation; Mice; Mice, Inbred C57BL; Mitochondria; Mitochondria - metabolism; Mitochondrial Proteins - genetics; Mitochondrial Proteins - metabolism; multidisciplinary; NADH-ubiquinone oxidoreductase; Ovalbumin; Ovalbumin - immunology; Respiration; Science; Science (multidisciplinary)
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-48653-y

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. Treatment failure following chimaeric antigen receptor (CAR) T cell therapy is common yet incompletely understood. In this study, the authors demonstrate that deletion of the mitochondrial negative regulator, MCJ, in CAR T cells promotes target cell killing ex vivo and augments their efficacy in an in vivo B cell leukaemia model.