Immunometabolite L-2-HG promotes epigenetic modification of exhausted T cells and improves antitumor immunity
Yanying Yang, Xiaoyan Li, Fangming Liu, Mingyue Ma, Ying Yang, Chengchao Ruan, Yan Lu, Xiaoyang Li, Xiangdong Wang, Yinghong Shi, Zheng Zhang, Hua Wang, Zhouli Cheng, Duojiao Wu
Yanying Yang, Xiaoyan Li, Fangming Liu, Mingyue Ma, Ying Yang, Chengchao Ruan, Yan Lu, Xiaoyang Li, Xiangdong Wang, Yinghong Shi, Zheng Zhang, Hua Wang, Zhouli Cheng, Duojiao Wu
View: Text | PDF
Research Article Immunology Metabolism

Immunometabolite L-2-HG promotes epigenetic modification of exhausted T cells and improves antitumor immunity

Abstract

This study aimed to explore the potential correlation between the metabolic intermediate L-2-hydroxyglutarate (L-2-HG) and T cell exhaustion, as well as the underlying mechanisms involved. In this study, we investigated the presence of exhausted T (Tex) cells in patients under certain conditions: HIV infection, chronic leukemia, and hepatocellular carcinoma. To gain insights into the epigenetic signatures and transcriptome changes in Tex cells, we employed a combination of RNA-seq and ATAC-seq analyses. To evaluate the impact of L-2-HG on mitochondrial function, differentiation, and antitumor capacity of Tex cells, we utilized in vitro cell culture experiments and animal tumor models. We observed mitochondrial depolarization and metabolic dysfunction in Tex cells, accompanied by a significant reduction in L-2-HG levels. Moreover, altered epigenetic characteristics were observed in Tex cells, including a substantial increase in H3K27me3 abundance. Culturing Tex cells with L-2-HG demonstrated improved mitochondrial metabolism, reduced H3K27me3 abundance, and enhanced memory T cell differentiation. In a mouse melanoma tumor model, L-2-HG–treated CD8+ T cells for adoptive therapy led to significantly reduced tumor volume and significantly enhanced effector function of T cells. The study revealed that L-2-HG acted as an immune metabolite through epigenetic modifications of Tex cells.

Authors

Yanying Yang, Xiaoyan Li, Fangming Liu, Mingyue Ma, Ying Yang, Chengchao Ruan, Yan Lu, Xiaoyang Li, Xiangdong Wang, Yinghong Shi, Zheng Zhang, Hua Wang, Zhouli Cheng, Duojiao Wu

×

Figure 6

L-2-HG treatment promotes antitumor immunity of TILs.

Options: View larger image (or click on image) Download as PowerPoint
L-2-HG treatment promotes antitumor immunity of TILs. (A) Schematic diag...
(A) Schematic diagram of adoptive transfer of PBS, Teff cells, or Teff cells plus L-2-HG into MO5 melanoma tumor–bearing CD45.1 mice on day 10 after inoculation. (B and C) CD45.1 mice were subcutaneously injected with MO5 melanoma cells and adopted with CD45.2 CD8+ T cells treated with PBS or L-2-HG. Tumor growth curves and survival of the mice were measured at indicated time points. (D) At 7 or 15 days after transfer, the number of transferred cells (CD45.1–CD45.2+ T cells) in the tumors of recipient mice were assessed using flow cytometry. PB, peripheral blood. (E) The mitochondrial status of tumor-infiltrating T cells labeled with MitoRed and MitoGreen at 7 days and 15 days. (F) The expression of IFN-γ in tumor tumor-infiltrating T cells by flow staining. n = 4–8 per group and each dot represents 1 sample. Data are represented as mean ± SEM. *P < 0.05; **P < 0.01; ***P < 0.001 by 1-way ANOVA. OVA, ovalbumin aa 257–264 peptide; PBS, PBS negative control; Teff, effector T cells; Teff+L-2-HG, effector T cells treated with 300 μM L-2-HG.