Synthetic RORγ agonists regulate multiple pathways to enhance antitumor immunity.

Area of Science:

• Immunology
• Molecular Biology
• Oncology

Background:

• RORγt is a key transcription factor for Th17 and Tc17 cells, crucial in anti-tumor immunity.
• RORγ+ cells constitute approximately 15% of CD4+ T cells within human tumors.

Purpose of the Study:

• To evaluate the role of RORγt in anti-tumor immunity.
• To identify and characterize novel small molecule agonists that selectively activate RORγt.

Main Methods:

• Developed synthetic RORγt agonists with greater potency than desmosterol.
• Assessed agonist effects on T cell function (cytokine production, receptor expression, survival, cytotoxicity) and tumor growth in vitro and in vivo.
• Confirmed on-target activity using RORγt-/- T cells.

Main Results:

• RORγt agonists enhanced Type 17 cell effector functions, increasing IL-17A and GM-CSF production, and augmenting co-stimulatory receptors.
• Agonists reduced immunosuppression by decreasing Treg formation, CD39/CD73 expression, and co-inhibitory receptors (PD-1, TIGIT).
• In vitro treated T cells showed enhanced anti-tumor activity upon adoptive transfer, controlling tumor growth and improving T cell persistence in vivo.

Conclusions:

• RORγt agonists demonstrate potent, immune system-dependent anti-tumor efficacy as single agents when administered orally.
• These agonists integrate multiple anti-tumor mechanisms, increasing immune activation and decreasing suppression for robust tumor growth inhibition.
• RORγt agonists represent a promising novel immunotherapy for cancer treatment.