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 3

ZFP91 disturbs antitumor activity of tumor-infiltrating T cells.

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ZFP91 disturbs antitumor activity of tumor-infiltrating T cells. (A and ...
(A and B) Gene ontology enrichment analysis of upregulated (Up) and downregulated (Down) gene sets in tumor-infiltrating CD8+ T cells (A) or CD4+ T cells (B) from Zfp91+/+ Cd4-Cre and Zfp91fl/fl Cd4-Cre mice (n = 6) that were s.c. injected with MC38 murine colon cancer cells (day 14). p.adjust, adjusted P value. (C) GSEA enrichment plots of the indicated signatures in tumor-infiltrating CD8+ T cells from Zfp91+/+ Cd4-Cre (WT) and Zfp91fl/fl Cd4-Cre (KO) mice (n = 6) that were s.c. injected with MC38 murine colon cancer cells (day 14). (D) Number of OT-I cells in tumor tissues from MC38-OVA tumor–bearing mice with transferred CFSE-labeled WT OT-I and CTV-labeled KO OT-I cells (on day 7 after adoptive transfer of OT-I cells) (n = 4). (E–G) Percentage and number of IFN-γ+ OT-I cells (E and F) or Ki-67+ OT-I cells (G) in tumor tissues from MC38-OVA tumor–bearing mice with transferred OT-I cells (on day 7 after adoptive transfer of OT-I cells) (n = 4). Experiments were independently repeated 4 times (D–G). Data are presented as the mean ± SEM. **P < 0.01, by 2-tailed Student’s t test.