Implications of a granulocyte-high glioblastoma microenvironment in immune suppression and therapy resistance^†

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. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.