Myeloid cells in glioblastoma microenvironment

Glioblastoma (GBM) is the most aggressive, malignant primary brain tumor in adults. GBM is notoriously resistant to immunotherapy mainly due to its unique immune microenvironment. High dimensional data analysis reveals the extensive heterogeneity of immune components making up the GBM microenvironment. Myeloid cells are the most predominant contributors to the GBM microenvironment; these cells are critical regulators of immune and therapeutic responses to GBM. Here, we will review the most recent advances on the characteristics and functions of different populations of myeloid cells in GBM, including bone marrow-derived macrophages, microglia, myeloid-derived suppressor cells, dendritic cells, and neutrophils. Epigenetic, metabolic, and phenotypic peculiarities of microglia and bone marrow-derived macrophages will also be assessed. The final goal of this review will be to provide new insights into novel therapeutic approaches for specific targeting of myeloid cells to improve the efficacy of current treatments in GBM patients

Patho- physiological role of BDNF in fibrin clotting

Circulating levels of Brain Derived Neurotrophic Factor (BDNF) are lower in coronary heart disease (CHD) than in healthy subjects and are associated with coronary events and mortality. However, the mechanism(s) underling this association is not fully understood. We hypothesize that BDNF may influence fibrin fiber structure and clot stability, favoring clot lysis and thrombus resolution. We showed that recombinant BDNF (rh-BDNF) influenced with clot formation in a concentration-dependent manner in both purified fibrinogen and plasma from healthy subjects. In particular, rh-BDNF reduced the density of fibrin fibers, the maximum clot firmness (MCF) and the maximum clot turbidity, and affected the lysis of clot. In addition, both thrombin and reptilase clotting time were prolonged by rh-BDNF, despite the amount of thrombin formed was greater. Intriguingly, CHD patients had lower levels of BDNF, greater fibrin fibers density, higher MCF than control subjects, and a negative correlation between BDNF and MCF was found. Of note, rh-BDNF markedly modified fibrin clot profile restoring physiological clot morphology in CHD plasma. In conclusion, we provide evidence that low levels of BDNF correlate with the formation of bigger thrombi (in vitro) and that this effect is mediated, at least partially, by the alteration of fibrin fibers formation

Polymorphonuclear myeloid-derived suppressor cells limit antigen crosspresentation by dendritic cells in cancer

DCs are a critical component of immune responses in cancer primarily due to their ability to cross-present tumor-associated antigens. Cross-presentation by DCs in cancer is impaired, which may represent one of the obstacles for the success of cancer immunotherapies. Here, we report that polymorphonuclear myeloid-derived suppressor cells (PMN-MDSC) blocked crosspresentation by DCs without affecting direct presentation of antigens by these cells. This effect did not require direct cell-cell contact and was associated with transfer of lipids. Neutrophils (PMN) and PMN-MDSC transferred lipid to DCs equally well; however, PMN did not affect DC cross-presentation. PMN-MDSC generate oxidatively truncated lipids previously shown to be involved in impaired cross-presentation by DCs. Accumulation of oxidized lipids in PMN-MDSC was dependent on myeloperoxidase (MPO). MPO-deficient PMN-MDSC did not affect cross-presentation by DCs. Cross-presentation of tumor-associated antigens in vivo by DCs was improved in MDSC-depleted or tumor-bearing MPO-KO mice. Pharmacological inhibition of MPO in combination with checkpoint blockade reduced tumor progression in different tumor models. These data suggest MPO-driven lipid peroxidation in PMN-MDSC as a possible non–cell autonomous mechanism of inhibition of antigen cross-presentation by DCs and propose MPO as potential therapeutic target to enhance the efficacy of current immunotherapies for patients with cancer