TSH-TSHR axis promotes tumor immune evasion

Background Hormones are identified as key biological variables in tumor immunity. However, previous researches mainly focused on the immune effect of steroid hormones, while the roles that thyroid-stimulating hormone (TSH) played in the antitumor response were far from clear. Methods The source of TSH was determined using single-cell transcriptomic, histologic, quantitative PCR, and ELISA analysis. The influence of TSH on tumor proliferation, invasion, and immune evasion was evaluated in multiple cell lines of thyroid cancer, glioma, and breast cancer. Then transcriptomic sequencing and cellular experiments were used to identify signaling pathways. TSH receptor (TSHR) inhibitor was injected into homograft mouse tumor models with or without anti-programmed cell death protein-1 antibody. Results Monocyte-derived dendritic cells (moDCs) highly expressed TSH alpha and TSH beta 2 and were the primary source of TSH in the tumor microenvironment. TSH released by moDCs promoted proliferation and invasion of tumors with high TSHR expressions, such as thyroid cancers and glioma. TSH also induced tumor programmed death-ligand 1 (PD-L1) expression through the TSHR-AC-PKA-JNK-c-JUN pathway. TSHR inhibitors reversed tumor immune evasion by inhibiting PD-L1 expression in tumor and myeloid cells and enhancing Teff activation. Conclusions TSH-TSHR axis promotes tumor evasion in thyroid cancers and glioma. TSH suppression therapy is an effective therapeutic strategy for combination in immune checkpoint blockades.

Automated summary

This study examines the role of thyroid-stimulating hormone (TSH) in tumor immunity. It finds that TSH promotes tumor growth and invasion in thyroid cancers and glioma through the TSH receptor (TSHR) pathway. TSH also induces the expression of programmed death-ligand 1 (PD-L1) in tumors, contributing to immune evasion. Inhibiting TSHR reverses tumor immune evasion and enhances T effector cell activation. These findings suggest that TSH suppression therapy could be an effective strategy in combination with immune checkpoint blockades.