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

• Published in: Cancer immunology research Vol. 9; no. 4; p. 454
• Main Authors: Xin, Gang, Chen, Yao, Topchyan, Paytsar, Kasmani, Moujtaba Y, Burns, Robert, Volberding, Peter J, Wu, Xiaopeng, Cohn, Alexandra, Chen, Yiliang, Lin, Chien-Wei, Ho, Ping-Chih, Silverstein, Roy, Dwinell, Michael B, Cui, Weiguo
• Format: Journal Article
• Language: English
• Published: United States 01.04.2021
• Subjects: Animals; B7-H1 Antigen - drug effects; B7-H1 Antigen - immunology; B7-H1 Antigen - metabolism; Biphenyl Compounds - pharmacology; CD8-Positive T-Lymphocytes - immunology; Cell Line, Tumor; Drug Resistance, Neoplasm; Female; Humans; Immune Checkpoint Inhibitors - pharmacology; Immunotherapy - methods; Male; Mice; Mice, Inbred C57BL; Myeloid-Derived Suppressor Cells - immunology; Myeloid-Derived Suppressor Cells - metabolism; Neoplasms, Experimental - metabolism; Proto-Oncogene Proteins c-pim-1 - genetics; Proto-Oncogene Proteins c-pim-1 - metabolism; Thiazolidines - pharmacology; Tumor Microenvironment - immunology
• DOI: 10.1158/2326-6066.CIR-20-0433

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 of 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.