The Interplay of Tumor Vessels and Immune Cells Affects Immunotherapy of Glioblastoma

Abstract

Immunotherapies with immune checkpoint inhibitors or adoptive cell transfer have become powerful tools to treat cancer. These treatments act via overcoming or alleviating tumor-induced immunosuppression, thereby enabling effective tumor clearance. Glioblastoma (GBM) represents the most aggressive, primary brain tumor that remains refractory to the benefits of immunotherapy. The immunosuppressive immune tumor microenvironment (TME), genetic and cellular heterogeneity, and disorganized vasculature hinder drug delivery and block effector immune cell trafficking and activation, consequently rendering immunotherapy ineffective. Within the TME, the mutual interactions between tumor, immune and endothelial cells result in the generation of positive feedback loops, which intensify immunosuppression and support tumor progression. We focus here on the role of aberrant tumor vasculature and how it can mediate hypoxia and immunosuppression. We discuss how immune cells use immunosuppressive signaling for tumor progression and contribute to the development of resistance to immunotherapy. Finally, we assess how a positive feedback loop between vascular normalization and immune cells, including myeloid cells, could be targeted by combinatorial therapies with immune checkpoint blockers and sensitize the tumor to immunotherapy.

Depletion of chitinase-3-like protein 1 (CHI3L1) in glioma cells restraints tumor growth and affects neovasculature in intracranial murine gliomas

“…Aberrant vasculature is a hallmark of GBM pathology. The tumor vessels are collapsed and disorganized, which contributes to hypoxia and immunosuppression, and creates speci c TME (16, [41][42][43]. The astrocytes are displaced by glioblastoma, which disrupts the blood-brain barrier and results in a damaging 'permeability and retention effect' (44).…”

Overcoming Barriers in Glioblastoma—Advances in Drug Delivery Strategies

“…However, some GBM characteristics have been reported to hamper an effective influx of leucocytes. For example, reductions in the expression of intracellular adhesion molecule 1 (ICAM1) and vascular cell adhesion molecule 1 (VCAM1) at the BBTB may prevent leucocyte tethering and extravasation [ 48 ]. Furthermore, cytokines expressed by the CECs can create an immunosuppressive environment that hampers leucocyte activation and extravasation [ 49 , 50 ].…”

Inflammatory Mediators and GBM Malignancy: Current Scenario and Future Prospective

“…; Table 2, Ref. [46][47][48][49][50][51][52][53][54][55][56][57][58][59][60][61]). It has been reported that blocking the activity of IL-6R by tocilizumab in a glioma cell line (U87MG) prevented cell proliferation by acting through the Janus kinase/signal transducer and activator of transcription 3 (JAK/STAT3) pathways [25].…”