Therapeutic Targeting of the Tumor Microenvironment.

Strategies to therapeutically target the tumor microenvironment (TME) have emerged as a promising approach for cancer treatment in recent years due to the critical roles of the TME in regulating tumor progression and modulating response to standard-of-care therapies. Here, we summarize the current knowledge regarding the most advanced TME-directed therapies, which have either been clinically approved or are currently being evaluated in trials, including immunotherapies, antiangiogenic drugs, and treatments directed against cancer-associated fibroblasts and the extracellular matrix. We also discuss some of the challenges associated with TME therapies, and future perspectives in this evolving field. SIGNIFICANCE: This review provides a comprehensive analysis of the current therapies targeting the TME, combining a discussion of the underlying basic biology with clinical evaluation of different therapeutic approaches, and highlighting the challenges and future perspectives.

Microglia contribute to the glia limitans around arteries, capillaries and veins under physiological conditions, in a model of neuroinflammation and in human brain tissue.

Microglia represent resident immune cells of the central nervous system (CNS), which have been shown to be involved in the pathophysiology of practically every neuropathology. As microglia were described to participate in the formation of the astroglial glia limitans around CNS vessels, they are part of the neurovascular unit (NVU). Since the NVU is a highly specialized structure, being functionally and morphologically adapted to differing demands in the arterial, capillary, and venous segments, the present study was aimed to systematically investigate the microglial contribution to the glia limitans along the vascular tree. Thereby, the microglial participation in the glia limitans was demonstrated for arteries, capillaries, and veins by immunoelectron microscopy in wild-type mice. Furthermore, analysis by confocal laser scanning microscopy revealed the highest density of microglial endfeet contacting the glial basement membrane around capillaries, with significantly lower densities around arteries and veins. Importantly, this pattern appeared to be unaltered in the setting of experimental autoimmune encephalomyelitis (EAE) in CX3CR1CreERT2:R26-Tomato reporter mice, although perivascular infiltrates of blood-borne leukocytes predominantly occur at the level of post-capillary venules. However, EAE animals exhibited significantly increased contact sizes of individual microglial endfeet around arteries and veins. Noteworthy, under EAE conditions, the upregulation of MHC-II was not limited to microglia of the glia limitans of veins showing infiltrates of leukocytes, but also appeared at the capillary level. As a microglial contribution to the glia limitans was also observed in human brain tissue, these findings may help characterizing microglial alterations within the NVU in various neuropathologies.