The HSP90 Inhibitor Pimitespib Targets Regulatory T Cells in the Tumor Microenvironment

Area of Science:

• Immunology
• Oncology
• Pharmacology

Background:

• Regulatory T (Treg) cells suppress anti-tumor immune responses and contribute to resistance against PD-1 blockade therapy.
• Heat shock protein 90 (HSP90) inhibition impacts cancer progression and may modulate anti-tumor immunity, but mechanisms are unclear.
• Understanding Treg cell modulation by HSP90 inhibitors is crucial for developing novel cancer immunotherapies.

Purpose of the Study:

• To investigate the effects of the HSP90 inhibitor pimitespib on Treg cells in cancer.
• To elucidate the mechanisms by which pimitespib affects Treg cell function and numbers.
• To evaluate the therapeutic potential of combining HSP90 inhibition with PD-1 blockade.

Main Methods:

• Treatment with the HSP90 inhibitor pimitespib in animal cancer models.
• Analysis of Treg cell populations and function in treated animals and patients with gastric cancer (EPOC1704 clinical trial).
• Mechanistic studies involving STAT5 signaling pathway and FOXP3 expression.

Main Results:

• Pimitespib selectively reduced Treg cell numbers in animal models and gastric cancer patients.
• Pimitespib inhibited proliferation and effector molecule expression of FOXP3high effector Treg cells, improving CD8+ T cell responses.
• Pimitespib degraded STAT5, compromising IL2 signaling, Treg cell maintenance, and FOXP3 expression, thereby impairing tumor immunosuppression.
• Combination therapy of pimitespib and PD-1 blockade showed superior anti-tumor effects compared to monotherapy.

Conclusions:

• HSP90 inhibition, specifically with pimitespib, offers a promising strategy for Treg cell-targeted cancer immunotherapy.
• Targeting HSP90 can selectively reduce immunosuppressive Treg cells within the tumor microenvironment.
• Combining HSP90 inhibitors with PD-1 blockade represents a potent therapeutic approach for enhancing anti-tumor immunity.