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 7

ZFP91 is required for PP2A activity in T cells.

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ZFP91 is required for PP2A activity in T cells. (A) Flow cytometric anal...
(A) Flow cytometric analysis of p-S6 levels in Zfp91+/+ Cd4-Cre (WT) and Zfp91fl/fl Cd4-Cre (KO) CD90.2+ T cells stimulated with anti-CD3 and anti-CD28 antibodies for 2 hours in the presence of SMase (0.5 U/mL) or control (50% glycerol in PBS). (B) ECAR of WT and KO T cells stimulated with anti-CD3 and anti-CD28 antibodies for 24 hours in the presence of SMase (n = 3) or control. (C and D) Flow cytometric analysis of cell size (C) and Ki-67 expression (D, n = 3) in WT and KO T cells stimulated with anti-CD3 and anti-CD28 antibodies for 24 hours (for FSC-A detection) or 48 hours (for Ki-67 detection) in the presence of SMase or control. (E) Flow cytometric analysis of p-S6 levels in WT and KO T cells stimulated with anti-CD3 and anti-CD28 antibodies for 2 hours in the presence of LB-100 (1 µM) or control. (F) ECAR of WT and KO T cells stimulated with anti-CD3 and anti-CD28 antibodies for 24 hours in the presence of LB-100 (1 µM) or control. (G and H) Flow cytometric analysis of cell size (G) and Ki-67 expression (H, n = 3) in WT and KO T cells stimulated with anti-CD3 and anti-CD28 antibodies for 24 hours (for FSC-A detection) or 48 hours (for Ki-67 detection) in the presence of LB-100 or control. (I) IB analysis of HA-PP2Ac in WT and KO T cells transduced with either an empty vector (EV) or PP2Ac. (J–M) p-S6 expression (J), ECAR (K, n = 4), cell size (L), and Ki-67 expression (M, n = 3) for transduced T cells from I stimulated for 2 hours (J), 24 hours (K and L), or 48 hours (M) with antibodies against CD3 and CD28. Experiments were independently repeated 3 times. Data are presented as the mean ± SEM. *P < 0.05 and **P < 0.01, by 2-tailed Student’s t test.