The failure of anti-VEGF/R and immune checkpoint therapies to improve overall survival in Phase III clinical trials in glioblastoma (GBM) is considered to be due in part to the prevalent immunosuppression in the GBM tumor microenvironment. Immune suppression is mediated in part by resident microglia and bone-marrow-derived myeloid cells recruited during tumor progression. A paper by Blank et al published in a recent issue of The Journal of Pathology proposes a myeloid cell-mediated mechanism that could contribute to resistance to anti-VEGF/R in GBM patients. A granulocyte-rich GBM tumor microenvironment may push the associated microglia/macrophages to exhibit an activated and immune suppressive phenotype. The identification of pro-angiogenic factors produced by microglia/macrophages and granulocytes in such a tumor microenvironment may offer new targets for improving antiangiogenic therapy of GBM beyond VEGF. Further, consideration of parameters such as IDH status, corticosteroid dosage, tumor mutational burden, gender, vascular function, and pericyte coverage could exploit current immunotherapies to the fullest to reprogram the granulocyte-rich immunosuppressive GBM tumor microenvironment to an immunostimulatory one. (c) 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

For a blood-borne cancer therapeutic agent to be effective, it must cross the blood vessel wall to reach cancer cells in adequate quantities, and it must overcome the resistance conferred by the local microenvironment around cancer cells. The brain microenvironment can thwart the effectiveness of drugs against primary brain tumours as well as brain metastases. In this Review, we highlight the cellular and molecular components of the blood-brain barrier (BBB), a specialized neurovascular unit evolved to maintain brain homeostasis. Tumours are known to compromise the integrity of the BBB, resulting in a vasculature known as the blood-tumour barrier (BTB), which is highly heterogeneous and characterized by numerous distinct features, including non-uniform permeability and active efflux of molecules. We discuss the challenges posed by the BBB and BTB for drug delivery, how multiple cell types dictate BBB function and the role of the BTB in disease progression and treatment. Finally, we highlight emerging molecular, cellular and physical strategies to improve drug delivery across the BBB and BTB and discuss their impact on improving conventional as well as emerging treatments, such as immune checkpoint inhibitors and engineered T cells. A deeper understanding of the BBB and BTB through the application of single-cell sequencing and imaging techniques, and the development of biomarkers of BBB integrity along with systems biology approaches, should enable new personalized treatment strategies for primary brain malignancies and brain metastases.

The limited efficacy of current antiangiogenic therapies calls for a better understanding of the specific resistance mechanisms in glioblastoma (GBM) and the urgent development of new therapeutic strategies targeting these pathways. In this issue of Cancer Research, Mastrella and colleagues reported that expression of the proangiogenic peptide apelin (APLN) was decreased and GBM cell invasion was increased after anti-VEGF therapy in preclinical models of GBM. Using the mutant form of the natural apelin-13 peptide, the authors showed reduction of both angiogenesis and invasion in the GBM models, and further increased the efficacy of anti-VEGF therapy. VEGF blockade is still widely used as salvage therapy for recurrent GBM, therefore these intriguing results have potential translational implications as they point to a potential new strategy to overcome VEGF blockade resistance; however, they also raise important questions for the clinical translation of this strategy, and its impact on antitumor responses, in particular immune responses.