Dendritic cell Piezo1 integrating mechanical stiffness and inflammatory signals directs the differentiation of T H 1 and T reg cells in cancer
Abstract
Dendritic cells (DCs) play an important role in anti-tumor immunity by inducing T cell differentiation. Herein, we found that the mechanical sensor Piezo1 expressed by DCs integrates innate inflammatory stimuli and stiffness signals and directs the reciprocal differentiation of T H 1 and regulatory T (T reg ) cells in cancer. Genetic deletion of Piezo1 in DCs inhibited the generation of T H 1 cells while driving the development of T reg cells in promoting cancer growth. 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 T reg and T H 1 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 T H 1 and T reg 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.
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Author Response
Reviewer #2 (Public Review):
The authors explored if and how Piezo1 regulated mechanical stiffness and inflammatory signals, thereby directing the differentiation of TH1 and Treg cells in cancer. They showed the genetic deletion of Piezo1, a mechanosensory ion channel, in dendritic cells, promoted tumor growth in a mouse model. Piezo1ΔDC mice showed an increase in Tregs and a decrease in IFNg+ Th1 cells in the MC38 tumor tissue. They showed TGFbR2-pSmad3 and IL-12Rb2-pStat4 signaling axis were involved in this process. Moreover, they suggested cooperation between Piezo1-SIRT1-HIF1a-glycolysis metabolism pathway and calcium-Piezo1-calcineurin-NFAT signaling pathway in DCs.
The authors have never directly tested the relationship between Piezo1 and DC stiffness. The authors claimed that "Piezo1 integrates innate …
Author Response
Reviewer #2 (Public Review):
The authors explored if and how Piezo1 regulated mechanical stiffness and inflammatory signals, thereby directing the differentiation of TH1 and Treg cells in cancer. They showed the genetic deletion of Piezo1, a mechanosensory ion channel, in dendritic cells, promoted tumor growth in a mouse model. Piezo1ΔDC mice showed an increase in Tregs and a decrease in IFNg+ Th1 cells in the MC38 tumor tissue. They showed TGFbR2-pSmad3 and IL-12Rb2-pStat4 signaling axis were involved in this process. Moreover, they suggested cooperation between Piezo1-SIRT1-HIF1a-glycolysis metabolism pathway and calcium-Piezo1-calcineurin-NFAT signaling pathway in DCs.
The authors have never directly tested the relationship between Piezo1 and DC stiffness. The authors claimed that "Piezo1 integrates innate inflammatory signals and mechanical stiffness signals". But what they showed were independent experiments of inflammatory stimulus (LPS) or stiffness stimulus (50kPa hydrogel). Do these two stimuli work together to induce Piezo1 signaling and contribute to Piezo-mediated differentiation of Th1 and Treg cells?
Following the reviewer’s suggestions and comments, we included the new data showing that different stiffness conditions or/and LPS can change Piezo1 expression in human DC cells (Fig. 7C). Accordingly, we also the revised the title and text and added the discussions in the revised manuscript.
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Evaluation Summary:
Wang and colleagues report that the expression of Piezo1 (an ion channel and mechanical sensor) is upregulated on dendritic cells (DC) under conditions of inflammation/high environmental stiffness resulting in DC activation, maturation, and skewing in DC functional polarity and metabolism. They show that Piezo1 knockout results in faster tumor progression and accumulation of more regulatory T cells, and that Smad3 and STAT4 are involved in DC-mediated differentiation of Th1 and Treg. Overall this represents a mechanistic advance in our understanding of DC biology as it relates to cancer and other human pathologies.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 and …
Evaluation Summary:
Wang and colleagues report that the expression of Piezo1 (an ion channel and mechanical sensor) is upregulated on dendritic cells (DC) under conditions of inflammation/high environmental stiffness resulting in DC activation, maturation, and skewing in DC functional polarity and metabolism. They show that Piezo1 knockout results in faster tumor progression and accumulation of more regulatory T cells, and that Smad3 and STAT4 are involved in DC-mediated differentiation of Th1 and Treg. Overall this represents a mechanistic advance in our understanding of DC biology as it relates to cancer and other human pathologies.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 and Reviewer #3 agreed to share their name with the authors.)
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Reviewer #1 (Public Review):
In the present study, the authors use mouse cancer models to study the role of Piezo1 on DC-mediated priming of CD4+ T cells. They show that Piezo1 knockout results in faster tumor progression and accumulation of more regulatory T cells, and that Smad3 and STAT4 are involved in DC-mediated differentiation of Th1 and Treg. Overall this represents a mechanistic advance in our understanding of DC biology as it relates to cancer.
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Reviewer #2 (Public Review):
The authors explored if and how Piezo1 regulated mechanical stiffness and inflammatory signals, thereby directing the differentiation of TH1 and Treg cells in cancer. They showed the genetic deletion of Piezo1, a mechanosensory ion channel, in dendritic cells, promoted tumor growth in a mouse model. Piezo1ΔDC mice showed an increase in Tregs and a decrease in IFNg+ Th1 cells in the MC38 tumor tissue. They showed TGFbR2-pSmad3 and IL-12Rb2-pStat4 signaling axis were involved in this process. Moreover, they suggested cooperation between Piezo1-SIRT1-HIF1a-glycolysis metabolism pathway and calcium-Piezo1-calcineurin-NFAT signaling pathway in DCs.
The authors have never directly tested the relationship between Piezo1 and DC stiffness. The authors claimed that "Piezo1 integrates innate inflammatory signals and …
Reviewer #2 (Public Review):
The authors explored if and how Piezo1 regulated mechanical stiffness and inflammatory signals, thereby directing the differentiation of TH1 and Treg cells in cancer. They showed the genetic deletion of Piezo1, a mechanosensory ion channel, in dendritic cells, promoted tumor growth in a mouse model. Piezo1ΔDC mice showed an increase in Tregs and a decrease in IFNg+ Th1 cells in the MC38 tumor tissue. They showed TGFbR2-pSmad3 and IL-12Rb2-pStat4 signaling axis were involved in this process. Moreover, they suggested cooperation between Piezo1-SIRT1-HIF1a-glycolysis metabolism pathway and calcium-Piezo1-calcineurin-NFAT signaling pathway in DCs.
The authors have never directly tested the relationship between Piezo1 and DC stiffness. The authors claimed that "Piezo1 integrates innate inflammatory signals and mechanical stiffness signals". But what they showed were independent experiments of inflammatory stimulus (LPS) or stiffness stimulus (50kPa hydrogel). Do these two stimuli work together to induce Piezo1 signaling and contribute to Piezo-mediated differentiation of Th1 and Treg cells?
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Reviewer #3 (Public Review):
The major strength of the report lies in its study of informative KO mice and targeted inhibitors to validate the involvement of Piezzo1 in host dendritic cells on T cell response and tumor growth outcomes. This allows the authors to confirm the importance of specific downstream mediators and signaling pathways in study results and to develop an operating paradigm for mechanisms of action mediated by Piezzo1 in DCs. The conclusions reached by the authors appear appropriate and represent an advance in the field.
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