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

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.

Microwave ablation of giant hepatic cavernous hemangiomas.

PURPOSE: This study was designed to explore the safety and efficacy of percutaneous microwave (MW) ablation as an alternative treatment for symptomatic giant hepatic hemangiomas. METHODS: Patients (n = 7; 6 females, 1 male; mean age = 44 years) with symptomatic, giant hemangiomas (n = 8) were treated with ultrasound-guided percutaneous MW ablation and followed for a mean of 18 months. Patient pain was recorded both before and after the procedure according to the 10-point visual analog scale. All patients were treated using one or three gas-cooled 17-gauge antennas powered by a 2.4-GHz generator (Neuwave Medical, Madison, WI). Mean ablation time was 11.6 min. Four patients received hydrodissection to protect the abdominal wall, colon, or gallbladder (5 % dextrose in water, mean volume 900 mL). Immediate postablation biphasic CT of the abdomen was performed, and four of seven patients have undergone delayed follow-up imaging. RESULTS: All ablations were technically successful with no major or minor complications. Average pain score decreased from 4.6 to 0.9 (p < 0.05), and six of seven patients report resolution or improvement of symptoms at 18-month average follow-up (range 1-33 months). Immediately postablation, mean tumor diameter decreased 25 % (from 7.3 to 5.5 cm, p < 0.05) and volume decreased 62 % (from 301 to 113 cm(3), p < 0.05). DISCUSSION: In this series, percutaneous MW ablation was safe, well-tolerated, and effective in markedly shrinking large hepatic hemangiomas and improving symptoms in most patients.