Dendritic cell Piezo1 stimulated by mechanical stiffness or inflammatory signals directs the differentiation of TH1 and Treg cells in cancer

  1. Yuexin Wang
  2. Hui Yang
  3. Anna Jia
  4. Yufei Wang
  5. Qiuli Yang
  6. Yingjie Dong
  7. Yueru Hou
  8. Yejin Cao
  9. Lin Dong
  10. Yujing Bi  Is a corresponding author
  11. Guangwei Liu  Is a corresponding author
  1. Beijing Normal University, China
  2. Fudan University, China
  3. Beijing Institute of Microbiology and Epidemiology, China

Abstract

Dendritic cells (DCs) play an important role in anti-tumor immunity by inducing T cell differentiation. Herein, we found that the DC mechanical sensor Piezo1 stimulated by mechanical stiffness or inflammatory signals directs the reciprocal differentiation of TH1 and regulatory T (Treg) cells in cancer. Genetic deletion of Piezo1 in DCs inhibited the generation of TH1 cells while driving the development of Treg cells in promoting cancer growth in mice. Mechanistically, Piezo1-deficient DCs regulated the secretion of the polarizing cytokines TGFβ1 and IL-12, leading to increased TGFβR2-p-Smad3 activity and decreased IL-12Rβ2-p-STAT4 activity while inducing the reciprocal differentiation of Treg and TH1 cells. In addition, Piezo1 integrated the SIRT1-hypoxia-inducible factor-1 alpha (HIF1α)-dependent metabolic pathway and calcium-calcineurin-NFAT signaling pathway to orchestrate reciprocal TH1 and Treg lineage commitment through DC-derived IL-12 and TGFβ1. Our studies provide critical insight for understanding the role of the DC-based mechanical regulation of immunopathology in directing T cell lineage commitment in tumor microenvironments.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files; Source Data files have provided for Fig.1.

Article and author information

Author details

  1. Yuexin Wang

    Beijing Normal University, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  2. Hui Yang

    Fudan University, Shanghai, China
    Competing interests
    The authors declare that no competing interests exist.
  3. Anna Jia

    Beijing Normal University, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  4. Yufei Wang

    Beijing Normal University, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  5. Qiuli Yang

    Beijing Normal University, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  6. Yingjie Dong

    Beijing Normal University, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  7. Yueru Hou

    Beijing Normal University, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  8. Yejin Cao

    Beijing Normal University, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  9. Lin Dong

    Beijing Normal University, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  10. Yujing Bi

    Beijing Institute of Microbiology and Epidemiology, Beijing, China
    For correspondence
    byj7801@sina.com
    Competing interests
    The authors declare that no competing interests exist.
  11. Guangwei Liu

    Beijing Normal University, Beijing, China
    For correspondence
    liugw@bnu.edu.cn
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6008-2891

Funding

National Natural Science Foundation for Key Programm of China (31730024)

  • Guangwei Liu

National Natural Science Foundation for General Program of China (32170911)

  • Guangwei Liu

Beijing Municipal Natural Science Foundation of China (5202013)

  • Guangwei Liu

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Kellie N Smith, The Johns Hopkins University School of Medicine, United States

Ethics

Animal experimentation: All animal experiments were approved by the Animal Ethics Committee of Fudan University, Shanghai, China, Beijing Institute of Microbiology and Epidemiology and Beijing Normal University (IACUC-DWZX-2017-003 and CLS-EAW-2017-002)

Human subjects: Normal human DCs (CC-2701; Lonza) and human cord blood CD4+ T cells (2C-200; Lonza) were obtained from Lonza Company. All human subject experiments were performed with the approval of the Ethics Committee of of Fudan University, China and Beijing Normal University, China.

Version history

  1. Received: May 3, 2022
  2. Preprint posted: May 18, 2022 (view preprint)
  3. Accepted: August 20, 2022
  4. Accepted Manuscript published: August 22, 2022 (version 1)
  5. Version of Record published: September 7, 2022 (version 2)

Copyright

© 2022, Wang et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 1,767
    views
  • 523
    downloads
  • 21
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Yuexin Wang
  2. Hui Yang
  3. Anna Jia
  4. Yufei Wang
  5. Qiuli Yang
  6. Yingjie Dong
  7. Yueru Hou
  8. Yejin Cao
  9. Lin Dong
  10. Yujing Bi
  11. Guangwei Liu
(2022)
Dendritic cell Piezo1 stimulated by mechanical stiffness or inflammatory signals directs the differentiation of TH1 and Treg cells in cancer
eLife 11:e79957.
https://doi.org/10.7554/eLife.79957

Share this article

https://doi.org/10.7554/eLife.79957

Further reading

    1. Cancer Biology
    2. Cell Biology
    Linda Zhang, Joanne I Hsu ... Margaret A Goodell
    Research Article

    The DNA damage response is critical for maintaining genome integrity and is commonly disrupted in the development of cancer. PPM1D (protein phosphatase Mg2+/Mn2+-dependent 1D) is a master negative regulator of the response; gain-of-function mutations and amplifications of PPM1D are found across several human cancers making it a relevant pharmacological target. Here, we used CRISPR/Cas9 screening to identify synthetic-lethal dependencies of PPM1D, uncovering superoxide dismutase-1 (SOD1) as a potential target for PPM1D-mutant cells. We revealed a dysregulated redox landscape characterized by elevated levels of reactive oxygen species and a compromised response to oxidative stress in PPM1D-mutant cells. Altogether, our results demonstrate a role for SOD1 in the survival of PPM1D-mutant leukemia cells and highlight a new potential therapeutic strategy against PPM1D-mutant cancers.

    1. Cancer Biology
    Haley R Noonan, Alexandra M Thornock ... Leonard I Zon
    Research Article

    Developmental signaling pathways associated with growth factors such as TGFb are commonly dysregulated in melanoma. Here we identified a human TGFb enhancer specifically activated in melanoma cells treated with TGFB1 ligand. We generated stable transgenic zebrafish with this TGFb Induced Enhancer driving green fluorescent protein (TIE:EGFP). TIE:EGFP was not expressed in normal melanocytes or early melanomas but was expressed in spatially distinct regions of advanced melanomas. Single-cell RNA-sequencing revealed that TIE:EGFP+ melanoma cells down-regulated interferon response while up-regulating a novel set of chronic TGFb target genes. ChIP-sequencing demonstrated that AP-1 factor binding is required for activation of chronic TGFb response. Overexpression of SATB2, a chromatin remodeler associated with tumor spreading, showed activation of TGFb signaling in early melanomas. Confocal imaging and flow cytometric analysis showed that macrophages localize to TIE:EGFP+ regions and preferentially phagocytose TIE:EGFP+ melanoma cells compared to TIE:EGFP- melanoma cells. This work identifies a TGFb induced immune response and demonstrates the need for the development of chronic TGFb biomarkers to predict patient response to TGFb inhibitors.