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The Sympathetic Nervous System Modulates Cancer Vaccine Activity through Monocyte-Derived Cells

Louis Hinkle, Yongbin Liu, Chaoyang Meng, Zhe Chen, Junhua Mai, Licheng Zhang, Yitian Xu, Ping-Ying Pan, Shu-Hsia Chen and Haifa Shen
J Immunol December 15, 2021, 207 (12) 3131-3140; DOI: https://doi.org/10.4049/jimmunol.2100719
Louis Hinkle
*Department of Nanomedicine, Houston Methodist Research Institute, Houston, TX;
†Texas A&M Health Science Center, Bryan, TX;
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Yongbin Liu
*Department of Nanomedicine, Houston Methodist Research Institute, Houston, TX;
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Chaoyang Meng
*Department of Nanomedicine, Houston Methodist Research Institute, Houston, TX;
‡Xiangya Hospital of Central South University, Changsha, Hunan, China;
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Zhe Chen
*Department of Nanomedicine, Houston Methodist Research Institute, Houston, TX;
‡Xiangya Hospital of Central South University, Changsha, Hunan, China;
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Junhua Mai
*Department of Nanomedicine, Houston Methodist Research Institute, Houston, TX;
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Licheng Zhang
§Center for Cancer Immunotherapy, Houston Methodist Research Institute, Houston, TX; and
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Yitian Xu
§Center for Cancer Immunotherapy, Houston Methodist Research Institute, Houston, TX; and
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Ping-Ying Pan
§Center for Cancer Immunotherapy, Houston Methodist Research Institute, Houston, TX; and
¶Weill Cornell Medical College, New York, NY
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Shu-Hsia Chen
§Center for Cancer Immunotherapy, Houston Methodist Research Institute, Houston, TX; and
¶Weill Cornell Medical College, New York, NY
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Haifa Shen
*Department of Nanomedicine, Houston Methodist Research Institute, Houston, TX;
¶Weill Cornell Medical College, New York, NY
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Key Points

  • β2-Adrenergic signaling impacts monocyte-derived cells rather than dendritic cells.

  • Propranolol improves cancer vaccine treatment of melanoma in mice.

Abstract

The sympathetic nervous system (SNS) is an important regulator of immune cell function during homeostasis and states of inflammation. Recently, the SNS has been found to bolster tumor growth and impair the development of antitumor immunity. However, it is unclear whether the SNS can modulate APC function. Here, we investigated the effects of SNS signaling in murine monocyte-derived macrophages (moMФ) and dendritic cells (DCs) and further combined the nonspecific β-blocker propranolol with a peptide cancer vaccine for the treatment of melanoma in mice. We report that norepinephrine treatment dramatically altered moMФ cytokine production, whereas DCs were unresponsive to norepinephrine and critically lack β2-adrenergic receptor expression. In addition, we show that propranolol plus cancer vaccine enhanced peripheral DC maturation, increased the intratumor proportion of effector CD8+ T cells, and decreased the presence of intratumor PD-L1+ myeloid-derived suppressor cells. Furthermore, this combination dramatically reduced tumor growth compared with vaccination alone. Taken together, these results offer insights into the cell-specific manner by which the SNS regulates the APC immune compartment and provide strong support for the use of propranolol in combination with cancer vaccines to improve patient response rates and survival.

This article is featured in Top Reads, p.

Footnotes

  • This work was supported by National Institutes of Health Grants U54CA210181 (to H.S.), R01CA193880 (to H.S.), and R01CA222959 (to H.S.). Additional funding sources include grants from the Houston Methodist Research Institute (to S.-H.C.) and a Houston Methodist Research Institute Emily Herrmann endowed chair in cancer immunotherapy (to S.-H.C.).

  • L.H. and H.S. initiated the project. L.H. carried out most of the studies, performed data analysis, and wrote the manuscript. Y.L., L.Z., Y.X., P.-Y.P., and S.-H.C. contributed to time-of-flight mass cytometry analyses. C.M., Z.C., and J.M. contributed to bone marrow–derived dendritic cell preparation. S.-H.C. and H.S. oversaw study design, data analysis, manuscript preparation, and manuscript review.

  • The online version of this article contains supplemental material.

  • Abbreviations used in this article

    β2AR
    β2-adrenergic receptor
    ArgI
    arginase I
    BMDC
    bone marrow–derived dendritic cell
    cDC
    conventional dendritic cell
    DC
    dendritic cell
    GPCR
    G protein–coupled receptor
    MC
    monocyte-derived cell
    MDSC
    myeloid-derived suppressor cell
    M-MDSC
    monocytic MDSC
    moDC
    monocyte-derived dendritic cell
    moMФ
    monocyte derived macrophage
    NOS2
    inducible NO synthase
    OT-I
    OVA257-264-specific CD8+ T cell
    PMN-MDSC
    polymorphonuclear MDSC
    poly I:C
    polyinosinic-polycytidylic acid
    poly ICLC
    polyinosinic-polycytidylic acid complexed with poly-l-lysine
    PS
    penicillin and streptomycin
    SNS
    sympathetic nervous system
    TAM
    tumor-associated macrophage
    TEM
    effector memory T cell

  • Received July 21, 2021.
  • Accepted October 5, 2021.
  • Copyright © 2021 by The American Association of Immunologists, Inc.
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The Journal of Immunology: 207 (12)
The Journal of Immunology
Vol. 207, Issue 12
15 Dec 2021
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The Sympathetic Nervous System Modulates Cancer Vaccine Activity through Monocyte-Derived Cells
Louis Hinkle, Yongbin Liu, Chaoyang Meng, Zhe Chen, Junhua Mai, Licheng Zhang, Yitian Xu, Ping-Ying Pan, Shu-Hsia Chen, Haifa Shen
The Journal of Immunology December 15, 2021, 207 (12) 3131-3140; DOI: 10.4049/jimmunol.2100719

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The Sympathetic Nervous System Modulates Cancer Vaccine Activity through Monocyte-Derived Cells
Louis Hinkle, Yongbin Liu, Chaoyang Meng, Zhe Chen, Junhua Mai, Licheng Zhang, Yitian Xu, Ping-Ying Pan, Shu-Hsia Chen, Haifa Shen
The Journal of Immunology December 15, 2021, 207 (12) 3131-3140; DOI: 10.4049/jimmunol.2100719
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