The neurotransmitter calcitonin gene-related peptide shapes an immunosuppressive microenvironment in medullary thyroid cancer

Yingtong Hou, Bo Lin, Tianyi Xu, Juan Jiang, Shuli Luo, Wanna Chen, Xinwen Chen, Yuanqi Wang, Guanrui Liao, Jianping Wang, Jiayuan Zhang, Xuyang Li, Xiao Xiang, Yubin Xie, Ji Wang, Sui Peng, Weiming Lv, Yihao Liu () and Haipeng Xiao ()
Additional contact information
Yingtong Hou: Sun Yat-Sen University
Bo Lin: Sun Yat-sen University
Tianyi Xu: Sun Yat-Sen University
Juan Jiang: Sun Yat-sen University
Shuli Luo: Sun Yat-Sen University
Wanna Chen: Sun Yat-sen University
Xinwen Chen: Sun Yat-Sen University
Yuanqi Wang: Sun Yat-sen University
Guanrui Liao: Sun Yat-sen University
Jianping Wang: Sun Yat-sen University
Jiayuan Zhang: Sun Yat-Sen University
Xuyang Li: Sun Yat-Sen University
Xiao Xiang: Sun Yat-sen University
Yubin Xie: Sun Yat-sen University
Ji Wang: Sun Yat-sen University
Sui Peng: Sun Yat-sen University
Weiming Lv: Sun Yat-sen University
Yihao Liu: Sun Yat-sen University
Haipeng Xiao: Sun Yat-Sen University

Nature Communications, 2024, vol. 15, issue 1, 1-19

Abstract: Abstract Neurotransmitters are key modulators in neuro-immune circuits and have been linked to tumor progression. Medullary thyroid cancer (MTC), an aggressive neuroendocrine tumor, expresses neurotransmitter calcitonin gene-related peptide (CGRP), is insensitive to chemo- and radiotherapies, and the effectiveness of immunotherapies remains unknown. Thus, a comprehensive analysis of the tumor microenvironment would facilitate effective therapies and provide evidence on CGRP’s function outside the nervous system. Here, we compare the single-cell landscape of MTC and papillary thyroid cancer (PTC) and find that expression of CGRP in MTC is associated with dendritic cell (DC) abnormal development characterized by activation of cAMP related pathways and high levels of Kruppel Like Factor 2 (KLF2), correlated with an impaired activity of tumor infiltrating T cells. A CGRP receptor antagonist could offset CGRP detrimental impact on DC development in vitro. Our study provides insights of the MTC immunosuppressive microenvironment, and proposes CGRP receptor as a potential therapeutic target.

Date: 2024
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DOI: 10.1038/s41467-024-49824-7

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