ZFP91 disturbs metabolic fitness and antitumor activity of tumor-infiltrating T cells
Feixiang Wang, Yuerong Zhang, Xiaoyan Yu, Xiao-Lu Teng, Rui Ding, Zhilin Hu, Aiting Wang, Zhengting Wang, Youqiong Ye, Qiang Zou
Feixiang Wang, Yuerong Zhang, Xiaoyan Yu, Xiao-Lu Teng, Rui Ding, Zhilin Hu, Aiting Wang, Zhengting Wang, Youqiong Ye, Qiang Zou
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Research Article Immunology Metabolism

ZFP91 disturbs metabolic fitness and antitumor activity of tumor-infiltrating T cells

Abstract

Proper metabolic activities facilitate T cell expansion and antitumor function; however, the mechanisms underlying disruption of the T cell metabolic program and function in the tumor microenvironment (TME) remain elusive. Here, we show a zinc finger protein 91–governed (ZFP91-governed) mechanism that disrupts the metabolic pathway and antitumor activity of tumor-infiltrating T cells. Single-cell RNA-Seq revealed that impairments in T cell proliferation and activation correlated with ZFP91 in tissue samples from patients with colorectal cancer. T cell–specific deletion of Zfp91 in mice led to enhanced T cell proliferation and potentiated T cell antitumor function. Loss of ZFP91 increased mammalian target of rapamycin complex 1 (mTORC1) activity to drive T cell glycolysis. Mechanistically, T cell antigen receptor–dependent (TCR-dependent) ZFP91 cytosolic translocation promoted protein phosphatase 2A (PP2A) complex assembly, thereby restricting mTORC1-mediated metabolic reprogramming. Our results demonstrate that ZFP91 perturbs T cell metabolic and functional states in the TME and suggest that targeting ZFP91 may improve the efficacy of cancer immunotherapy.

Authors

Feixiang Wang, Yuerong Zhang, Xiaoyan Yu, Xiao-Lu Teng, Rui Ding, Zhilin Hu, Aiting Wang, Zhengting Wang, Youqiong Ye, Qiang Zou

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Figure 1

Impairments in T cell proliferation and activation are correlated with ZFP91 in CRC.

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Impairments in T cell proliferation and activation are correlated with Z...
(A) The heatmap shows the average mRNA expression of ZFP91, and the violin plot shows the distribution of ZFP91 mRNA expression in different cell types from 7 scRNA-Seq data sets for COAD. B, B cells; CD4 Tconv, CD4+ conventional T cells; CD8 T, CD8+ T cells; CD8 Tex, exhausted CD8+ T cells; Mast, mast cells; Mono/Macro, monocytes and macrophages; NK, natural killer cells; Mki67+ T, proliferating Mki67+ T cells; pDC, plasmacytoid DCs. (B) Spearman’s correlation of mRNA expression of Zfp91 and the GSVA score for negative regulation of T cell proliferation in TCGA COAD database. (C and D) GSEA of the signature genes for the regulation of CD8+ αβ T cell proliferation (C) and αβ T cell activation (D) in ZFP91-expressing and ZFP91-silenced T cells. NES, normalization enrichment score. (E and F) qRT-PCR analysis of genes associated with T cell proliferation (E) and activation (F) in tumor-infiltrating T cells from CRC. The normalized Zfp91 expression value of tumor-infiltrating T cells with the lowest expression of Zfp91 was set at 1. The normalized Zfp91 expression values of Zfp91hi T cells were higher than 2 (n = 4), and those of Zfp91lo T cells were less than 2 (n = 6). Data in E and F are representative of 3 independent experiments. Data are represented as the mean ± SEM. *P < 0.05 and **P < 0.01 by calculated by permutation test (C and D) and 2-tailed Student’s t test (E and F).