Transcriptional and metabolic reprogramming induce an inflammatory phenotype in non-medullary thyroid carcinoma-induced macrophages

• Published in: Oncoimmunology 2016-12, Vol.5 (12), p.e1229725-e1229725
• Main Authors: Arts, Rob J. W., Plantinga, Theo S., Tuit, Sander, Ulas, Thomas, Heinhuis, Bas, Tesselaar, Marika, Sloot, Yvette, Adema, Gosse J., Joosten, Leo A. B., Smit, Johannes W. A., Netea, Mihai G., Schultze, Joachim L., Netea-Maier, Romana T.
• Format: Article
• Language: English
• Subjects: Cytokines; epigenetics; immunometabolism; lactate; Original Research; thyroid cancer; tumor-associated macrophages
• ISSN: 2162-4011; 2162-402X; 2162-402X
• DOI: 10.1080/2162402X.2016.1229725

Tumor-associated macrophages (TAMs) are key components of the tumor microenvironment in non-medullary thyroid cancer (TC), the most common endocrine malignancy. However, little is known regarding the regulation of their function in TC. Transcriptome analysis in a model of TC-induced macrophages identified increased inflammatory characteristics and rewiring of cell metabolism as key functional changes. This functional reprogramming was partly mediated by TC-derived lactate that induced upregulation of cytokine production through an AKT1/mTOR-dependent increase in aerobic glycolysis. This led to epigenetic modifications at the level of histone methylation, and subsequently long-term functional changes. Immunohistochemistry assessment validated the increase in glycolysis enzymes and lactate receptor in TAMs in tissue samples from patients with TC. In conclusion, Akt/mTOR-dependent glycolysis mediates TC-induced reprogramming of TAMs and inflammation, and this may represent a novel therapeutic target in TC.