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Hormone hampers cancer immunity

Cancer immunotherapy has made great progress in recent years, but many tumors do not respond to any of the available immune treatments for reasons that are often unclear. Among other factors, the neuroendocrine system has been emerging as a potential influence on antitumor immune responses. Xu et al. examined the connections between hypothalamic-pituitary signaling and antitumor immunity, focusing on the role of α-melanocyte–stimulating hormone (α-MSH), which is produced by the pituitary gland. α-MSH promoted the accumulation of immunosuppressive cells, and its inhibition helped to suppress tumor growth in mouse models, suggesting it as a potential therapeutic approach. —YN

Abstract

The hypothalamic–pituitary (HP) unit can produce various hormones to regulate immune responses, and some of its downstream hormones or effectors are elevated in cancer patients. We show that the HP unit can promote myelopoiesis and immunosuppression to accelerate tumor growth. Subcutaneous implantation of tumors induced hypothalamus activation and pituitary α-melanocyte-stimulating hormone (α-MSH) production in mice. α-MSH acted on bone marrow progenitors to promote myelopoiesis, myeloid cell accumulation, immunosuppression, and tumor growth through its melanocortin receptor MC5R. MC5R peptide antagonist boosted antitumor immunity and anti–programmed cell death protein 1 (anti–PD-1) immunotherapy. Serum α-MSH concentration was elevated and correlated with circulating myeloid-derived suppressor cells in cancer patients. Our results reveal a neuroendocrine pathway that suppresses tumor immunity and suggest MC5R as a potential target for cancer immunotherapy.

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Supplementary Materials

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Materials and Methods
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References and Notes

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Volume 377 | Issue 6610
2 September 2022

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Received: 30 April 2021
Accepted: 22 July 2022
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Acknowledgments

We thank Y. Ma and S. Zhu for providing cell lines. We thank L. Zong, M. Ma, and B. Lin for technical support and all other members in the Zhou lab for helpful discussions.
Funding: This research was supported by the National Key Research and Development Program of China (grants 2019YFA0508503 and 2020YFA0509101), the Strategic Priority Research Program of the Chinese Academy of Sciences (grant XDB29030102), the National Natural Science Foundation of China (grants 81821001 and 82130107), the CAS Project for Young Scientists in Basic Research (YSBR-074), and the Fundamental Research Funds for the Central Universities and the University Synergy Innovation Program of Anhui Province (GXXT-2019-026).
Author contributions: Y.X., J.Y., Y.T., C.Z., L.Y., and X.Q. performed the experiments of this work. Y.X., J.Y., P.G., Y.L., Y.P., R.T., W.J., and R.Z. designed the research. Y.X., J.Y., R.T., W.J., and R.Z. wrote the manuscript. W.J. and R.Z. supervised the project.
Competing interests: R.T. is an employee of Jiangsu Simcere Pharmaceutical Company, Ltd. Y.X., J.Y., W.J., and R.Z. are co-inventors of a pending patent application (202110566828.3) submitted by University of Science and Technology of China that covers the function of MC5R and the antitumor effect of MC5R antagonist. All other authors declare that they have no competing interests.
Data and materials availability: All data are available in the main text or the supplementary materials. All the cell lines generated in this study are available from the authors.
License information: Copyright © 2022 the authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original US government works. https://www.science.org/about/science-licenses-journal-article-reuse

Authors

Affiliations

Hefei National Research Center for Physical Sciences at the Microscale, The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China.
Roles: Conceptualization, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Supervision, Validation, Visualization, Writing - original draft, and Writing - review & editing.
Hefei National Research Center for Physical Sciences at the Microscale, The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China.
Roles: Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Software, Supervision, Validation, Visualization, Writing - original draft, and Writing - review & editing.
Department of Otolaryngology–Head and Neck Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China.
Roles: Methodology and Resources.
Xiaojun Qian
Department of Oncology, The First Affiliated Hospital of University of Science and Technology of China, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, China.
Roles: Investigation and Resources.
Chi Zhang
Hefei National Research Center for Physical Sciences at the Microscale, The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China.
Role: Validation.
Hefei National Research Center for Physical Sciences at the Microscale, The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China.
Roles: Formal analysis, Investigation, and Validation.
Department of Geriatrics, Gerontology Institute of Anhui Province, The First Affiliated Hospital of University of Science and Technology of China, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, China.
Roles: Conceptualization and Methodology.
Department of Otolaryngology–Head and Neck Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China.
Role: Resources.
Yueyin Pan
Department of Oncology, The First Affiliated Hospital of University of Science and Technology of China, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, China.
Role: Resources.
State Key Laboratory of Translational Medicine and Innovative Drug Development, Nanjing 21000, China.
Roles: Conceptualization, Methodology, Project administration, Supervision, Visualization, and Writing - review & editing.
Hefei National Research Center for Physical Sciences at the Microscale, The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China.
Roles: Funding acquisition, Project administration, Supervision, Visualization, Writing - original draft, and Writing - review & editing.
Hefei National Research Center for Physical Sciences at the Microscale, The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China.
Insitute of Health and Medicine, Hefei Comprehensive National Science Center, Hefei 230601 China.
Roles: Conceptualization, Data curation, Funding acquisition, Methodology, Project administration, Supervision, Visualization, Writing - original draft, and Writing - review & editing.

Funding Information

National Key Research and Development Program of China: 2019YFA0508503
National Key Research and Development Program of China: 2020YFA0509101
Anhui Province: GXXT-2019-026

Notes

*
Corresponding author. Email: [email protected] (R.Z.); [email protected] (W.J.); [email protected] (R.T.)
These authors contributed equally to this work.

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