CXCR2 inhibition in G-MDSCs enhances CD47 blockade for melanoma tumor cell clearance.

The use of colony-stimulating factor-1 receptor (CSF1R) inhibitors has been widely explored as a strategy for cancer immunotherapy due to their robust depletion of tumor-associated macrophages (TAMs). While CSF1R blockade effectively eliminates TAMs from the solid tumor microenvironment, its clinical efficacy is limited. Here, we use an inducible CSF1R knockout model to investigate the persistence of tumor progression in the absence of TAMs. We find increased frequencies of granulocytic myeloid-derived suppressor cells (G-MDSCs) in the bone marrow, throughout circulation, and in the tumor following CSF1R deletion and loss of TAMs. We find that G-MDSCs are capable of suppressing macrophage phagocytosis, and the elimination of G-MDSCs through CXCR2 inhibition increases macrophage capacity for tumor cell clearance. Further, we find that combination therapy of CXCR2 inhibition and CD47 blockade synergize to elicit a significant anti-tumor response. These findings reveal G-MDSCs as key drivers of tumor immunosuppression and demonstrate their inhibition as a potent strategy to increase macrophage phagocytosis and enhance the anti-tumor efficacy of CD47 blockade in B16-F10 melanoma.

Modeling Glioma Intratumoral Heterogeneity with Primary Human Neural Stem and Progenitor Cells.

Glioblastoma multiforme (GBM) is a deadly form of glioma notable for its significant intratumoral heterogeneity, which is believed to drive therapy resistance. GBM has been observed to mimic a neural stem cell hierarchy reminiscent of normal brain development. However, it is still unclear how cell-of-origin shapes intratumoral heterogeneity. Here, we develop a model of glioma initiation using neural stem and progenitor cells (NSPCs) purified from fetal human brain tissue. We previously described a method to prospectively isolate and culture tripotent neural stem cells (NSCs), bipotent glial progenitor cells (GPCs), and unipotent oligodendrocyte precursor cells (OPCs). We transduced these isogenic lines with dominant-negative TP53 R175H and NF1 knockdown, a commonly-used genetic model of GBM in mice. These reprogrammed lines robustly engrafted when transplanted into the brains of immunodeficient mice, and showed significant expansion over time. Engrafted cells were reextracted from the mouse brain for single cell RNA sequencing (scRNA-seq), in order to quantify how the cell-of-origin modulates the cellular subtypes found in the resulting tumor. This result revealed the strong influence the cell-of-origin plays in glioma heterogeneity. Our platform is highly adaptable and allows for modular and systematic interrogation of how cell-of-origin shape the tumor landscape.

Zidebactam restores sulbactam susceptibility against carbapenem-resistant Acinetobacter baumannii isolates.

Carbapenems are commonly used to treat infections caused by multidrug-resistant (MDR) bacteria. Unfortunately, carbapenem resistance is increasingly reported in many gram-negative bacteria, especially Acinetobacter baumannii. Diazabicyclooctane (DBO) ß-lactamase inhibitors, such as avibactam (AVI), when combined with sulbactam successfully restore sulbactam susceptibility against certain carbapenem-resistant A. baumannii (CRAB) isolates. In the present study, we tested zidebactam, a novel DBO with an additional mechanism of action, in combination with sulbactam against CRAB isolates, including strains that exhibited resistance against sulbactam/avibactam combination. A panel of 43 geographically and genetically distinct CRAB isolates recovered from different hospitals and containing different mechanisms of resistance were included in the present study. We also tested three reference strains (AB0057, AB5075, and AYE). Minimum inhibitory concentrations (MICs) for sulbactam (range 0.12-512 mg/l) and sulbactam plus 4 mg/l zidebactam were performed using microdilution according to CLSI Standards. A decrease ≥2 dilutions in sulbactam MICs was observed in 84% of the isolates when tested in combination with zidebactam. The sulbactam/zidebactam combination was able to restore sulbactam susceptibility in 91% of the isolates, including isolates that were resistant to sulbactam/avibactam combination. These data encouraged us to further explore sulbactam/zidebactam in other experimental models especially against CRAB isolates resistant to other DBOs.

A New Twist: The Combination of Sulbactam/Avibactam Enhances Sulbactam Activity against Carbapenem-Resistant Acinetobacter baumannii (CRAB) Isolates.

An increasing number of untreatable infections are recorded every year. Many studies have focused their efforts on developing new ß-lactamase inhibitors to treat multi-drug resistant (MDR) isolates. In the present study, sulbactam/avibactam and sulbactam/relebactam combination were tested against 187 multi-drug resistant (MDR) Acinetobacter clinical isolates; both sulbactam/avibactam and sulbactam/relebactam restored sulbactam activity. A decrease ≥2 dilutions in sulbactam MICs was observed in 89% of the isolates when tested in combination with avibactam. Sulbactam/relebactam was able to restore sulbactam susceptibility in 40% of the isolates. In addition, the susceptibility testing using twenty-three A. baumannii AB5075 knockout strains revealed potential sulbactam and/or sulbactam/avibactam target genes. We observed that diazabicyclooctanes (DBOs) ß-lactamase inhibitors combined with sulbactam restore sulbactam susceptibility against carbapenem-resistant Acinetobacter clinical isolates. However, relebactam was not as effective as avibactam when combined with sulbactam. Exploring novel combinations may offer new options to treat Acinetobacter spp. infections, especially for widespread oxacillinases and metallo-ß-lactamases (MBLs) producers.