TY - JOUR
T1 - The Sympathetic Nervous System Modulates Cancer Vaccine Activity through Monocyte-Derived Cells
AU - Hinkle, Louis
AU - Liu, Yongbin
AU - Meng, Chaoyang
AU - Chen, Zhe
AU - Mai, Junhua
AU - Zhang, Licheng
AU - Xu, Yitian
AU - Pan, Ping Ying
AU - Chen, Shu Hsia
AU - Shen, Haifa
N1 - Funding Information:
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.).
Publisher Copyright:
© 2021 by The American Association of Immunologists, Inc.
PY - 2021/12/15
Y1 - 2021/12/15
N2 - 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 (moMA) and dendritic cells (DCs) and further combined the nonspecific b-blocker propranolol with a peptide cancer vaccine for the treatment of melanoma in mice. We report that norepinephrine treatment dramatically altered moMA cytokine production, whereas DCs were unresponsive to norepinephrine and critically lack b2-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.
AB - 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 (moMA) and dendritic cells (DCs) and further combined the nonspecific b-blocker propranolol with a peptide cancer vaccine for the treatment of melanoma in mice. We report that norepinephrine treatment dramatically altered moMA cytokine production, whereas DCs were unresponsive to norepinephrine and critically lack b2-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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U2 - 10.4049/jimmunol.2100719
DO - 10.4049/jimmunol.2100719
M3 - Article
C2 - 34772699
AN - SCOPUS:85134345739
SN - 0022-1767
VL - 207
SP - 3131
EP - 3140
JO - Journal of Immunology
JF - Journal of Immunology
IS - 12
ER -