Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
  • Clinical Research and Public Health
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Video Abstracts
  • Reviews
    • View all reviews ...
    • Pancreatic Cancer (Jul 2025)
    • Complement Biology and Therapeutics (May 2025)
    • Evolving insights into MASLD and MASH pathogenesis and treatment (Apr 2025)
    • Microbiome in Health and Disease (Feb 2025)
    • Substance Use Disorders (Oct 2024)
    • Clonal Hematopoiesis (Oct 2024)
    • Sex Differences in Medicine (Sep 2024)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Clinical Research and Public Health
    • Research Letters
    • Letters to the Editor
    • Editorials
    • Commentaries
    • Editor's notes
    • Reviews
    • Viewpoints
    • 100th anniversary
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Video Abstracts
  • In-Press Preview
  • Clinical Research and Public Health
  • Research Letters
  • Letters to the Editor
  • Editorials
  • Commentaries
  • Editor's notes
  • Reviews
  • Viewpoints
  • 100th anniversary
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
ZFP91 disturbs metabolic fitness and antitumor activity of tumor-infiltrating T cells
Feixiang Wang, … , Youqiong Ye, Qiang Zou
Feixiang Wang, … , Youqiong Ye, Qiang Zou
Published August 17, 2021
Citation Information: J Clin Invest. 2021;131(19):e144318. https://doi.org/10.1172/JCI144318.
View: Text | PDF
Research Article Immunology Metabolism Article has an altmetric score of 2

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

  • Text
  • PDF
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

×

Figure 5

ZFP91 suppresses T cell glycolytic metabolism.

Options: View larger image (or click on image) Download as PowerPoint
ZFP91 suppresses T cell glycolytic metabolism.
(A) Heatmap of upregulate...
(A) Heatmap of upregulated genes associated with T cell glycolysis in ZFP91-deficient T cells relative to gene expression in WT T cells stimulated with anti-CD3 and anti-CD28 antibodies for 24 hours. (B) ECAR of Zfp91+/+ Cd4-Cre and Zfp91fl/fl Cd4-Cre CD4+ or CD8+ T cells stimulated with anti-CD3 and anti-CD28 antibodies for 24 hours, at baseline (Bas) and in response to glucose (Glu), oligomycin (Oli), and 2-DG (n = 3 or 4). Max, maximum. (C) OCRs of Zfp91+/+ Cd4-Cre and Zfp91fl/fl Cd4-Cre CD4+ or CD8+ T cells stimulated with anti-CD3 and anti-CD28 antibodies for 24 hours, at baseline and in response to oligomycin, FCCP, and rotenone plus antimycin (R+A) (n = 3–4). (D) Flow cytometric analysis of cell size (forward scatter area [FSC-A]) for Zfp91+/+ Cd4-Cre and Zfp91fl/fl Cd4-Cre CD4+ or CD8+ T cells stimulated with anti-CD3 and anti-CD28 antibodies for 24 hours. (E) Flow cytometric analysis of Glut1 expression in T cells in tumors from Zfp91+/+ Cd4-Cre and Zfp91fl/fl Cd4-Cre mice injected s.c. with MC38 murine colon cancer cells (day 14). (F) Number of Glut1+ OT-I cells in the spleen and tumor from MC38-OVA tumor–bearing mice transferred with OT-I cells (on day 7 after adoptive transfer of OT-I cells) (n = 4). (G and H) ELISA of IFN-γ and IL-2 in supernatants (G, n = 4) and flow cytometric analysis of Ki-67 expression (H, n = 3) in Zfp91+/+ Cd4-Cre (WT) and Zfp91fl/fl Cd4-Cre (KO) T cells stimulated with anti-CD3 and anti-CD28 (α-CD3/CD28) antibodies for 48 hours in the presence of 2-DG (2 mM) or control (Ctrl). Experiments were independently repeated 3 times. Data are presented as the mean ± SEM. **P < 0.01, by 2-tailed Student’s t test.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts

Posted by 4 X users
19 readers on Mendeley
See more details