Bulk RNA sequencing of WT and Pim1 -/- bone-marrow-derived myeloid-derived suppressor cells

There is a strong correlation between myeloid derived suppressor cells (MDSCs) and resistance to immune checkpoint blockade (ICB), but the detailed underlying this correlation are largely unknown. Using single-cell RNA-seq analysis in a bilateral tumor model, we found that immunosuppressive myeloid cells with characteristics of fatty acid oxidative metabolism dominate the immune-cell landscape in ICB-resistant subjects. In addition, we uncovered a previously underappreciated role of a serine/threonine kinase, PIM1, in regulating lipid oxidative metabolism via PPAR?-mediated activities. Enforced PPAR? expression sufficiently rescued metabolic and functional defects of Pim1-/- MDSCs. Consistent with this, pharmacological inhibition of PIM kinase by AZD1208 treatment significantly disrupted myeloid cell–mediated immunosuppression microenvironment and unleashed CD8+ T cell–mediated antitumor immunity, which enhanced PD-L1 blockade in preclinical cancer models. PIM kinase inhibition also sensitized non-responders to PD-L1 blockade by selectively targeting suppressive myeloid cells. Overall, we have identified PIM1 as a metabolic modulator in MDSCs that is associated with ICB resistance and can be therapeutically targeted to overcome ICB resistance. Overall design: Bulk RNA sequencing, 2 samples (WT and Pim1-/- MDSC), 3 biological replicates per sample, from bone-marrow-derived myeloid-derived suppressor cells