Journal Article

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

Jiang, Juan, Peng, Sui, Wang, Ji, Li, Xuyang, Chen, Wanna, Luo, Shuli, Lv, Weiming, Chen, Xinwen, Wang, Jianping, Zhang, Jiayuan, Xu, Tianyi, Wang, Yuanqi, Xie, Yubin, Xiang, Xiao, Liu, Yihao, Xiao, Haipeng, Lin, Bo, Liao, Guanrui, Hou, Yingtong

2024

Overview

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. Medullary thyroid cancer (MTC) is a neuroendocrine tumor that originates from thyroid parafollicular cells, generally associated with a poor prognosis. By comparing MTC with less aggressive papillary thyroid cancer, here the authors find that the neurotransmitter calcitonin gene-related peptide (CGRP) promotes an immunosuppressive microenvironment in MTC.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/51 / 45/91 / 49/31 / 49/39 / 631/67/580 / 692/4028/67/1459/1843 / 692/4028/67/327 / C cells / Calcitonin / Calcitonin gene-related peptide / Calcitonin Gene-Related Peptide - metabolism / Calcitonin Gene-Related Peptide Receptor Antagonists - pharmacology / Cancer / Carcinoma, Neuroendocrine - genetics / Carcinoma, Neuroendocrine - immunology / Carcinoma, Neuroendocrine - metabolism / Carcinoma, Neuroendocrine - pathology / Cell activation / Cell Line, Tumor / Cyclic AMP - metabolism / Dendritic cells / Dendritic Cells - immunology / Dendritic Cells - metabolism / Effectiveness / Gene Expression Regulation, Neoplastic / Humanities and Social Sciences / Humans / Immunomodulation / Immunosuppressive agents / Immunotherapy / Krueppel-like factor / Lymphocytes / Lymphocytes T / Lymphocytes, Tumor-Infiltrating - immunology / Lymphocytes, Tumor-Infiltrating - metabolism / Modulators / multidisciplinary / Nervous system / Neuroendocrine tumors / Neuromodulation / Neurotransmitter Agents - metabolism / Neurotransmitters / Papillary thyroid cancer / Peptides / Radiation therapy / Receptors / Receptors, Calcitonin Gene-Related Peptide - metabolism / Science / Science (multidisciplinary) / Single-Cell Analysis / Therapeutic targets / Thyroid / Thyroid cancer / Thyroid Cancer, Papillary - genetics / Thyroid Cancer, Papillary - immunology / Thyroid Cancer, Papillary - metabolism / Thyroid Cancer, Papillary - pathology / Thyroid Neoplasms - genetics / Thyroid Neoplasms - immunology / Thyroid Neoplasms - metabolism / Thyroid Neoplasms - pathology / Tumor microenvironment / Tumor Microenvironment - immunology / Tumors