D2HGDH-mediated D2HG catabolism enhances the anti-tumor activities of CAR-T cells in an immunosuppressive microenvironment

• Published in: Molecular therapy 2022-03, Vol.30 (3), p.1188-1200
• Main Authors: Yang, Quanjun, Hao, Juan, Chi, Mengyi, Wang, Yaxian, Li, Jie, Huang, Jinlu, Zhang, Jianping, Zhang, Mengqi, Lu, Jin, Zhou, Shumin, Yuan, Ting, Shen, Zan, Zheng, Shuier, Guo, Cheng
• Format: Article
• Language: English
• Subjects: Alcohol Oxidoreductases - metabolism; Animals; Cell Line, Tumor; Cell Proliferation; chimeric antigen receptor; Cytokines - metabolism; D-2-hydroxyglutarate; D2HGDH; Glutarates - metabolism; Humans; Immunotherapy; Immunotherapy, Adoptive; Mice; Neoplasms - therapy; oncometabolites; Original; T-Lymphocytes - metabolism; Tumor Microenvironment
• ISSN: 1525-0016; 1525-0024
• DOI: 10.1016/j.ymthe.2022.01.007

The effect of immunotherapy is limited by oncometabolite D-2-hydroxyglutarate (D2HG). D2HGDH is an inducible enzyme that converts D2HG into the endogenous metabolite 2-oxoglutarate. We aimed to evaluate the impairment of CD8 T lymphocyte function in the high-D2HG environment and to explore the phenotypic features and anti-tumor effect of D2HGDH-modified CAR-T cells. D2HG treatment inhibited the expansion of human CD8 T lymphocytes and CAR-T cells, increased their glucose uptake, suppressed effector cytokine production, and decreased the central memory cell proportion. D2HGDH-modified CAR-T cells displayed distinct phenotypes, as D2HGDH knock-out (KO) CAR-T cells exhibited a significant decrease in central memory cell differentiation and intracellular cytokine production, while D2HGDH over-expression (OE) CAR-T cells showed predominant killing efficacy against NALM6 cancer cells in high-D2HG medium. In vivo xenograft experiments confirmed that D2HGDH-OE CAR-T cells decreased serum D2HG and improved the overall survival of mice bearing NALM6 cancer cells with mutation IDH1. Our findings demonstrated that the immunosuppressive effect of D2HG and distinct phenotype of D2HGDH modified CAR-T cells. D2HGDH-OE CAR-T cells can take advantage of the catabolism of D2HG to foster T cell expansion, function, and anti-tumor effectiveness. [Display omitted] Guo et al. reveal the immunosuppressive effect of D2HG and explore the phenotypic characteristics of modified CAR-T cells through knock-out and over-expression of D2HGDH. D2HGDH over-expression in CAR-T cells improves the killing effect against cancer cells through the potential of metabolic adaptability in an immunosuppressive environment.