LXR/ApoE Activation Restricts Innate Immune Suppression in Cancer

Area of Science:

• Immunology
• Oncology
• Pharmacology

Background:

• Cancer immunotherapy, particularly checkpoint inhibition, has revolutionized treatment but faces limited response rates.
• Non-responders often exhibit high levels of immunosuppressive myeloid-derived suppressor cells (MDSCs).

Purpose of the Study:

• To identify and target pathways regulating MDSC abundance to improve cancer immunotherapy efficacy.
• To investigate the therapeutic potential of liver-X nuclear receptor (LXR) agonism in reducing MDSCs and enhancing anti-tumor immunity.

Main Methods:

• Utilized genetic and pharmacological approaches to study MDSC regulation in murine cancer models.
• Conducted a first-in-human, dose escalation phase 1 trial of LXR agonism in cancer patients.
• Assessed MDSC levels, cytotoxic T lymphocyte (CTL) responses, and the role of ApoE.

Main Results:

• Therapeutic LXR agonism significantly reduced MDSC abundance in both mice and human patients.
• MDSC depletion correlated with enhanced CTL activation in preclinical and clinical settings.
• The LXR target ApoE mediated these effects, with LXR/ApoE activation promoting anti-tumor responses and T cell activation.

Conclusions:

• The LXR/ApoE axis is a key regulator of innate immune suppression in cancer.
• Targeting the LXR/ApoE pathway represents a promising strategy to enhance the efficacy of cancer immunotherapy.