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Synthetic RORγ agonists regulate multiple pathways to enhance antitumor immunity.

Xiao Hu1, Xikui Liu1, Jacques Moisan1

  • 1Lycera Corp , Ann Arbor, MI, USA.

Oncoimmunology
|January 27, 2017
PubMed
Summary

Small molecule agonists targeting RORγt (Retinoid-related Orphan Receptor gamma t) enhance anti-tumor immunity by boosting Type 17 cell function and reducing immune suppression. These RORγt agonists show promise as a novel cancer immunotherapy.

Keywords:
Adoptive cell therapyPD-1RORγTc17Th17co-inhibitory receptorsco-stimulatory receptorsimmunotherapy

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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.