The Role of Myeloid Cells in GBM Immunosuppression

Abstract

Gliomas are intrinsic brain tumors that originate from glial cells. Glioblastoma (GBM) is the most aggressive glioma type and resistant to immunotherapy, mainly due to its unique immune environment. Dimensional data analysis reveals that the intra-tumoral heterogeneity of immune cell populations in the glioma microenvironment is largely made up of cells of myeloid lineage. Conventional therapies of combined surgery, chemotherapy and radiotherapy have achieved limited improvements in the prognosis of glioma patients, as myeloid cells are prominent mediators of immune and therapeutic responses—like immunotherapy resistance—in glioma. Myeloid cells are frequently seen in the tumor microenvironment (TME), and they are polarized to promote tumorigenesis and immunosuppression. Reprogramming myeloid cells has emerged as revolutionary, new types of immunotherapies for glioma treatment. Here we detail the current advances in classifying epigenetic, metabolic, and phenotypic characteristics and functions of different populations of myeloid cells in glioma TME, including myeloid-derived suppressor cells (MDSCs), glioma-associated microglia/macrophages (GAMs), glioma-associated neutrophils (GANs), and glioma-associated dendritic cells (GADCs), as well as the mechanisms underlying promotion of tumorigenesis. The final goal of this review will be to provide new insights into novel therapeutic approaches for specific targeting of myeloid cells to improve the efficacy of current treatments in glioma patients.

Neutrophils in glioma microenvironment: from immune function to immunotherapy

“…Compared to neutrophils in peripheral blood, TANs were enriched with the angiogenesis-related factor S100A9 and MMP9 ( 153 ). Neutrophil-released BV8, S100A8/9, and MMP9 are key factors in activating VEGF-A, thereby promoting angiogenesis ( 159 ). Furthermore, Neutrophils can induce drug resistance in gliomas.…”

Exploring Monocytes-Macrophages in Immune Microenvironment of Glioblastoma for the Design of Novel Therapeutic Strategies

“…VEGF induced Ang-1 pericytes’ recruitment to improve vascular stability. Moreover, these molecules also participate in the recruitment of myeloid cell populations into GBM [ 26 , 27 ]. Around necrotic zone, Ang-1 is absent because hypoxia down-regulates Ang-1 expression; nevertheless, Ang-1 is more perceived in the tumor periphery [ 28 ].…”

“…Studies have shown that TAMs are highly implicated in suppressing anti-tumor immune functions of T cells and directly facilitate tumor cell immune escape [ 123 ]. For these reasons, as the higher macrophage infiltration in the TME of GBM is often correlated with poor treatment outcomes and prognosis [ 27 ], depleting them by specifically targeting and killing them is an attractive strategy that was evaluated in the recent past.…”

Emerging Nano‐Immunotherapeutic Approaches to Glioma

“…[47,48] As the richest nucleated hematopoietic cells, myeloid cells are the main regulators in glioma immunosuppression. [49] Myeloid cells at an immature status often differentiate into dendritic cells (DCs), macrophages, and granulocytes under normal conditions. However, some regulatory molecules under pathological conditions suppress the maturation of myeloid cells, resulting in the development of myeloid-derived suppressor cells (MDSCs) consisting of granulocytic and monocytic subsets.…”