| Autor: |
Weiguo Cui, Michael B. Dwinell, Roy Silverstein, Ping-Chih Ho, Chien-Wei Lin, Yiliang Chen, Alexandra Cohn, Xiaopeng Wu, Peter J. Volberding, Robert Burns, Moujtaba Y. Kasmani, Paytsar Topchyan, Yao Chen, Gang Xin |
| Rok vydání: |
2023 |
| DOI: |
10.1158/2326-6066.c.6550266.v1 |
| Popis: |
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. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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