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Tumor-derived high-mobility group box 1 and thymic stromal lymphopoietin are involved in modulating dendritic cells to activate T regulatory cells in a mouse model

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Abstract

High-mobility group box 1 (HMGB1) is involved in the tumor-associated activation of regulatory T cells (Treg), but the mechanisms remain unknown. In a mouse tumor model, silencing HMGB1 in tumor cells or inhibiting tumor-derived HMGB1 not only dampened the capacity of tumor cells to produce thymic stromal lymphopoietin (TSLP), but also aborted the tumor-associated modulation of Treg-activating DC. Tumor-derived HMGB1 triggered the production of TSLP by tumor cells. Importantly, both tumor-derived HMGB1 and TSLP were necessary for modulating DC to activate Treg in a TSLP receptor (TSLPR)-dependent manner. In the therapeutic model, intratumorally inhibiting tumor-derived HMGB1 (causing downstream loss of TSLP production) attenuated Treg activation, unleashed tumor-specific CD8 T cell responses, and elicited CD8α+/CD103+DC- and T cell-dependent antitumor activity. These results suggest a new pathway for the activation of Treg involving in tumor-derived HMGB1 and TSLP, and have important implications for incorporating HMGB1 inhibitors into cancer immunotherapy.

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Abbreviations

APC:

Antigen-presenting cells

Box A:

An antagonist for HMGB1

EP:

Ethyl pyruvate

GL:

Glycyrrhizin

HMGB1:

High-mobility group box 1

I.t.:

Intratumorally

KD:

Knockdown

KI:

Knockin

shRNA:

Short hairpin RNA

SPC:

Splenocytes

TDLN:

Tumor-draining lymph nodes

Th1 CD4+ :

T helper 1

Th2 CD4+ :

T helper 2

TME:

Tumor microenvironment

Treg Foxp3+ :

T regulatory cells

TSLP:

Thymic stromal lymphopoietin

TSLPR:

TSLP receptor

WB:

Western blot

WT:

Wild type

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Acknowledgements

We are indebted to Steven F. Ziegler (Benaroya Research Institute) for providing critical experimental materials which were prepared by Whitney Xu at the laboratory of Steven F. Ziegler, Dewayne Falkner at Flow Cytometry Core Facility (University of Pittsburgh) for assisting in flow cytometry and cell sorting, and Stephen C. Balmert at the laboratory of Louis D. Falo, Jr. for editing the manuscript. This work was supported by Department of Dermatology at The University of Pittsburgh School of Medicine and NIH Grants R21CA191522 (Zhaoyang You) and P50CA121973 (Louis D. Falo, Jr.).

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Author notes

  1. Yi Zhang

    Present address: The 3rd Affiliated Hospital of Jianghan University, Wuhan, China

  2. Yi Zhang, Zuqiang Liu and Xingxing Hao are contributed equally to this work.

Authors and Affiliations

  1. Department of Dermatology, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15213, USA

    Yi Zhang, Zuqiang Liu, Xingxing Hao, Jiying Zhang, Cara D. Carey, Louis D. Falo & Zhaoyang You

  2. Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15213, USA

    Zhaoyang You

  3. Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15213, USA

    Zuqiang Liu

  4. University of Pittsburgh Cancer Institute, Pittsburgh, PA, 15213, USA

    Zuqiang Liu, Louis D. Falo & Zhaoyang You

  5. Cleveland Clinic, Cole Eye Institute, 9500 Euclid Ave, Cleveland, OH, 44195, USA

    Ang Li

  6. W1154 Thomas E. Starzl Biomedical Science Tower, 200 Lothrop Street, Pittsburgh, PA, 15213, USA

    Zhaoyang You

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Zhang, Y., Liu, Z., Hao, X. et al. Tumor-derived high-mobility group box 1 and thymic stromal lymphopoietin are involved in modulating dendritic cells to activate T regulatory cells in a mouse model. Cancer Immunol Immunother 67, 353–366 (2018). https://doi.org/10.1007/s00262-017-2087-7

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