Targeting PIM1-Mediated Metabolism in Myeloid Suppressor Cells to Treat Cancer

Area of Science:

• Immunology
• Cancer Biology
• Metabolism

Background:

• Myeloid-derived suppressor cells (MDSC) are strongly correlated with resistance to immune checkpoint blockade (ICB).
• The precise mechanisms linking MDSC to ICB resistance remain largely undefined.

Purpose of the Study:

• To elucidate the mechanisms by which MDSC contribute to ICB resistance.
• To identify potential therapeutic targets for overcoming ICB resistance mediated by MDSC.

Main Methods:

• Single-cell RNA sequencing analysis in a bilateral tumor model.
• Investigation of the role of serine/threonine kinase PIM1 in regulating lipid metabolism.
• Pharmacologic inhibition of PIM kinase using AZD1208 in preclinical cancer models.

Main Results:

• Immunosuppressive myeloid cells with fatty acid oxidative metabolism characteristics were identified in ICB-resistant subjects.
• PIM1 was found to regulate lipid oxidative metabolism via PPARγ-mediated pathways.
• AZD1208 treatment disrupted the immunosuppressive myeloid cell microenvironment, enhancing CD8+ T-cell antitumor immunity and PD-L1 blockade efficacy.
• PIM1 kinase inhibition sensitized nonresponders to PD-L1 blockade by targeting suppressive myeloid cells.

Conclusions:

• PIM1 acts as a metabolic modulator in MDSC, contributing to ICB resistance.
• Targeting PIM1 kinase represents a promising therapeutic strategy to overcome ICB resistance by modulating MDSC function and enhancing anti-tumor immunity.