American Association for Cancer Research
23266066cir200433-sup-243945_2_supp_6804165_qls477.pdf (18.09 MB)

Supplemental Figures 1-8 from Targeting PIM1-Mediated Metabolism in Myeloid Suppressor Cells to Treat Cancer

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journal contribution
posted on 2023-04-04, 01:03 authored by Gang Xin, Yao Chen, Paytsar Topchyan, Moujtaba Y. Kasmani, Robert Burns, Peter J. Volberding, Xiaopeng Wu, Alexandra Cohn, Yiliang Chen, Chien-Wei Lin, Ping-Chih Ho, Roy Silverstein, Michael B. Dwinell, Weiguo Cui

Supplemental Figures 1-8 plus Legends






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 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.

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