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.

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.

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

  • 2,263
    views
  • 637
    downloads
  • 47
    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
    Qianqian Ju, Wenjing Sheng ... Cheng Sun
    Research Article

    TAK1 is a serine/threonine protein kinase that is a key regulator in a wide variety of cellular processes. However, the functions and mechanisms involved in cancer metastasis are still not well understood. Here, we found that TAK1 knockdown promoted esophageal squamous cancer carcinoma (ESCC) migration and invasion, whereas TAK1 overexpression resulted in the opposite outcome. These in vitro findings were recapitulated in vivo in a xenograft metastatic mouse model. Mechanistically, co-immunoprecipitation and mass spectrometry demonstrated that TAK1 interacted with phospholipase C epsilon 1 (PLCE1) and phosphorylated PLCE1 at serine 1060 (S1060). Functional studies revealed that phosphorylation at S1060 in PLCE1 resulted in decreased enzyme activity, leading to the repression of phosphatidylinositol 4,5-bisphosphate (PIP2) hydrolysis. As a result, the degradation products of PIP2 including diacylglycerol (DAG) and inositol IP3 were reduced, which thereby suppressed signal transduction in the axis of PKC/GSK-3β/β-Catenin. Consequently, expression of cancer metastasis-related genes was impeded by TAK1. Overall, our data indicate that TAK1 plays a negative role in ESCC metastasis, which depends on the TAK1-induced phosphorylation of PLCE1 at S1060.

    1. Cancer Biology
    2. Cell Biology
    Xiangning Bu, Nathanael Ashby ... Inhee Chung
    Research Article

    Cell crowding is a common microenvironmental factor influencing various disease processes, but its role in promoting cell invasiveness remains unclear. This study investigates the biomechanical changes induced by cell crowding, focusing on pro-invasive cell volume reduction in ductal carcinoma in situ (DCIS). Crowding specifically enhanced invasiveness in high-grade DCIS cells through significant volume reduction compared to hyperplasia-mimicking or normal cells. Mass spectrometry revealed that crowding selectively relocated ion channels, including TRPV4, to the plasma membrane in high-grade DCIS cells. TRPV4 inhibition triggered by crowding decreased intracellular calcium levels, reduced cell volume, and increased invasion and motility. During this process, TRPV4 membrane relocation primed the channel for later activation, compensating for calcium loss. Analyses of patient-derived breast cancer tissues confirmed that plasma membrane-associated TRPV4 is specific to high-grade DCIS and indicates the presence of a pro-invasive cell volume reduction mechanotransduction pathway. Hyperosmotic conditions and pharmacologic TRPV4 inhibition mimicked crowding-induced effects, while TRPV4 activation reversed them. Silencing TRPV4 diminished mechanotransduction in high-grade DCIS cells, reducing calcium depletion, volume reduction, and motility. This study uncovers a novel pro-invasive mechanotransduction pathway driven by cell crowding and identifies TRPV4 as a potential biomarker for predicting invasion risk in DCIS patients.