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.
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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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