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Targeting PIM1-Mediated Metabolism in Myeloid Suppressor Cells to Treat Cancer. Cancer Immunol Res 2021 Apr;9(4):454-469

Date

02/14/2021

Pubmed ID

33579728

Pubmed Central ID

PMC8137571

DOI

10.1158/2326-6066.CIR-20-0433

Scopus ID

2-s2.0-85104420312 (requires institutional sign-in at Scopus site)   13 Citations

Abstract

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 PPARĪ³-mediated activities. Enforced PPARĪ³ expression sufficiently rescued metabolic and functional defects of Pim1 -/- MDSCs. Consistent with this, pharmacologic inhibition of PIM kinase by AZD1208 treatment significantly disrupted the myeloid cell-mediated immunosuppressive microenvironment and unleashed CD8+ T-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.

Author List

Xin G, Chen Y, Topchyan P, Kasmani MY, Burns R, Volberding PJ, Wu X, Cohn A, Chen Y, Lin CW, Ho PC, Silverstein R, Dwinell MB, Cui W

Authors

Yiliang Chen PhD Assistant Professor in the Medicine department at Medical College of Wisconsin
Michael B. Dwinell PhD Director, Professor in the Microbiology and Immunology department at Medical College of Wisconsin
Chien-Wei Lin PhD Assistant Professor in the Institute for Health and Equity department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
B7-H1 Antigen
Biphenyl Compounds
CD8-Positive T-Lymphocytes
Cell Line, Tumor
Drug Resistance, Neoplasm
Female
Humans
Immunotherapy
Male
Mice
Mice, Inbred C57BL
Myeloid-Derived Suppressor Cells
Neoplasms, Experimental
Proto-Oncogene Proteins c-pim-1
Thiazolidines
Tumor Microenvironment