TET2 promotes tumor antigen presentation and T cell IFN-γ, which is enhanced by vitamin C
Meng Cheng, … , Yue Xiong, Albert S. Baldwin
Meng Cheng, … , Yue Xiong, Albert S. Baldwin
Published October 10, 2024
Citation Information: JCI Insight. 2024;9(22):e175098. https://doi.org/10.1172/jci.insight.175098.
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Research Article Immunology Oncology

TET2 promotes tumor antigen presentation and T cell IFN-γ, which is enhanced by vitamin C

Abstract

Immune evasion by tumors is promoted by low T cell infiltration, ineffective T cell activity directed against the tumor, and reduced tumor antigen presentation. The TET2 DNA dioxygenase gene is frequently mutated in hematopoietic malignancies and loss of TET enzymatic activity is found in a variety of solid tumors. We showed previously that vitamin C (VC), a cofactor of TET2, enhances tumor-associated T cell recruitment and checkpoint inhibitor therapy responses in a TET2-dependent manner. Using single-cell RNA sequencing (scRNA-seq) analysis performed on B16-OVA melanoma tumors, we have shown here that an additional function for TET2 in tumors is to promote expression of certain antigen presentation machinery genes, which is potently enhanced by VC. Consistently, VC promoted antigen presentation in cell-based and tumor assays in a TET2-dependent manner. Quantifying intercellular signaling from the scRNA-seq dataset showed that T cell–derived IFN-γ–induced signaling within the tumor and tumor microenvironment requires tumor-associated TET2 expression, which is enhanced by VC treatment. Analysis of patient tumor samples indicated that TET activity directly correlates with antigen presentation gene expression and with patient outcomes. Our results demonstrate the importance of tumor-associated TET2 activity as a critical mediator of tumor immunity, which is augmented by high-dose VC therapy.

Authors

Meng Cheng, Angel Ka Yan Chu, Zhijun Li, Shiyue Yang, Matthew D. Smith, Qi Zhang, Nicholas G. Brown, William F. Marzluff, Nabeel Bardeesy, J. Justin Milner, Joshua D. Welch, Yue Xiong, Albert S. Baldwin

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Figure 1

Injection of VC i.v. provides optimal, TET2-dependent anti–PD-L1 immunotherapy efficacy.

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Injection of VC i.v. provides optimal, TET2-dependent anti–PD-L1 immunot...
WT B16-OVA (2 × 105) cells were transplanted into 6-week-old C57BL/6J syngeneic mice followed by indicated doses of VC treatment daily or 200 μg anti–PD-L1 3 times per week. Tumor volume (A) was measured (width2 × length/2) with a caliper and mouse survival (B) was monitored and data recorded every day. Error bars represent ± SEM, n = 10. (C) TET2-KO clones of CT-26 cells were made using the CRISPR/Cas9 system and were confirmed by Western blotting as well as DNA sequencing; TET2 expression in CT-26 cells did not affect its proliferation in culture medium, n = 5. CT-26 (2 × 105) cells were transplanted into 6-week-old BALB/c syngeneic mice followed by 1 g/kg i.v. VC treatment every day or 200 μg anti–PD-L1 3 times per week as indicated. Tumor volume (D) was measured with a caliper and mouse survival (E) was monitored and data recorded each day. The P values shown in the tables for survival data were determined by log-rank (Mantel-Cox) test comparing each 2 groups or unpaired, 2-tailed Student’s t test, and multiple comparisons were corrected using Bonferroni’s method. Error bars represent ± SEM, n = 10. Statistical significance was defined as an adjusted P value (Bonferroni’s correction) of less than 0.05. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001. NS, no significance.