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  1. 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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  2. 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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  3. 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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  4. 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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  5. 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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