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

Feb 13, 2021Cancer immunology research

Targeting PIM1-Controlled Metabolism in Immune Suppressor Cells to Treat Cancer

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Circadian Biology on OpenScience ↗PubMed ↗DOI ↗

Abstract

A strong correlation exists between myeloid-derived suppressor cells (MDSC) and resistance to immune checkpoint blockade (ICB).

Immunosuppressive myeloid cells with fatty acid oxidative metabolism characteristics dominate in ICB-resistant subjects.
PIM1 is identified as a key regulator of lipid oxidative metabolism in MDSCs through its activities involving PPARγ.
Enforcing PPARγ expression can restore metabolic and functional deficiencies in MDSCs.
Inhibition of PIM kinase using AZD1208 disrupts the immunosuppressive environment created by myeloid cells.
Targeted inhibition of PIM kinase may enhance CD8 T-cell-mediated antitumor immunity and improve responses to PD-L1 blockade.

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There is a strong correlation between myeloid-derived suppressor cells (MDSC) and resistance to immune checkpoint blockade (ICB), but the detailed mechanisms underlying this correlation are largely unknown. Using single-cell RNA sequencing 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 PPARγ-mediated activities. Enforced PPARγ expression sufficiently rescued metabolic and functional defects ofMDSCs. Consistent with this, pharmacologic inhibition of PIM kinase by AZD1208 treatment significantly disrupted the myeloid cell-mediated immunosuppressive microenvironment and unleashed CD8T-cell-mediated antitumor immunity, which enhanced PD-L1 blockade in preclinical cancer models. PIM kinase inhibition also sensitized nonresponders 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. Pim1 -/-+

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

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