Monocyte-neutrophil entanglement in glioblastoma

Abstract

Glioblastoma (GBM) is the most belligerent and frequent brain tumor in adults. Research over the past two decades has provided increased knowledge of the genomic and molecular landscape of GBM and highlighted the presence of a high degree of inter- and intratumor heterogeneity within the neoplastic compartment. It is now appreciated that GBMs are composed of multiple distinct and impressionable neoplastic and non-neoplastic cell types that form the unique brain tumor microenvironment (TME). Non-neoplastic cells in the TME form reciprocal interactions with neoplastic cells to promote tumor growth and invasion, and together they influence the tumor response to standard-of-care therapies as well as emerging immunotherapies. One of the most prevalent non-neoplastic cell types in the GBM TME are myeloid cells, the most abundant of which are of hematopoietic origin, including monocytes/monocyte-derived macrophages. Less abundant, although still a notable presence, are neutrophils of hematopoietic origin and intrinsic brain-resident microglia. In this Review we focus on neutrophils and monocytes that infiltrate tumors from the blood circulation, their heterogeneity, and their interactions with neoplastic cells and other non-neoplastic cells in the TME. We conclude with an overview of challenges in targeting these cells and discuss avenues for therapeutic exploitation to improve the dismal outcomes of patients with GBM.

Figure 1. Inter- and intratumor heterogeneity of neoplastic and non-neoplastic compartments of GBM.

Genetic and molecular heterogeneity in GBM occurs at multiple levels: between patients (intertumor) and within the tumor from the same patient (intratumor). Inter- and intratumor heterogeneity exists both in neoplastic cells and in the tumor microenvironment, especially in the myeloid compartment.

Figure 2. Monocyte and neutrophil origins in health and GBM.

(A) Granulopoiesis and monocytopoiesis in mice. Monocytes and neutrophils are continuously generated in the bone marrow (BM) from hematopoietic stem cells (HSCs) via common myeloid progenitors (CMPs), giving rise to granulocyte-monocyte progenitors (GMPs). GMPs, via macrophage and dendritic cell (DC) precursor (MDP) and common monocyte progenitor (cMoP) cells, then give rise to functionally distinct Ly6C^hiCCR2^hiCXCR1^lo and Ly6C^loCCR2^–CXCR1^hi monocyte subsets that enter the blood circulation. GMPs, under the control of the granulocyte colony–stimulating factor (G-CSF), commit to neutrophil generation by turning into myeloblasts, which then follow a maturation process that includes the stages of promyelocyte, myelocyte, metamyelocyte, band cell, and finally a mature Ly6G^hiCXCR4^hiCXCR2^lo neutrophil. In healthy mice, both monocyte populations have short half-lives in circulation, including approximately 19 hours for inflammatory and approximately 2.2 days for patrolling monocytes (132), similar to what was shown for human monocytes, with the exception of a slightly longer lifespan for patrolling monocytes of approximately 4–7 days (133). Human neutrophil lifespan is estimated to be approximately 19 hours (134) to 5.4 days (135), and for mice approximately 12 hours (136). (B) Spatial distribution of myeloid subsets in GBM TME. Schematic illustration of the presence of various myeloid subsets in specialized areas of the TME, including perivascular, perinecrotic, and invasive edges of GBM. The neutrophil versus monocyte ratio of 1:7 in GBM is the opposite of their presence in blood (7:1). Neutrophils are predominantly localized in the necrotic core, and monocytes and monocytes that have differentiated into monocyte-derived macrophages are in perivascular and perinecrotic areas, while the majority of microglia are in the invasive edge of tumors.

Figure 3. Myeloid-mediated mechanisms of T cell immunosuppression.

Myeloid cells have developed several mechanisms to induce T cell suppression, including the induction/expansion of Tregs (top left), direct inhibition via cell contact (bottom left), depletion of nutrients from the tumor microenvironment (top right), induction of an oxidative stress state (middle right), and interfering with trafficking and infiltration and decreasing the viability of T cells (bottom right). The labels MDSC and PMN-MDSC in navy indicate whether studies of the mechanism shown were specific for PMN-MDSCs.