Origin, activation, and targeted therapy of glioma-associated macrophages

Abstract

The glioma tumor microenvironment plays a crucial role in the development, occurrence, and treatment of gliomas. Glioma-associated macrophages (GAMs) are the most widely infiltrated immune cells in the tumor microenvironment (TME) and one of the major cell populations that exert immune functions. GAMs typically originate from two cell types-brain-resident microglia (BRM) and bone marrow-derived monocytes (BMDM), depending on a variety of cytokines for recruitment and activation. GAMs mainly contain two functionally and morphologically distinct activation types- classically activated M1 macrophages (antitumor/immunostimulatory) and alternatively activated M2 macrophages (protumor/immunosuppressive). GAMs have been shown to affect multiple biological functions of gliomas, including promoting tumor growth and invasion, angiogenesis, energy metabolism, and treatment resistance. Both M1 and M2 macrophages are highly plastic and can polarize or interconvert under various malignant conditions. As the relationship between GAMs and gliomas has become more apparent, GAMs have long been one of the promising targets for glioma therapy, and many studies have demonstrated the therapeutic potential of this target. Here, we review the origin and activation of GAMs in gliomas, how they regulate tumor development and response to therapies, and current glioma therapeutic strategies targeting GAMs.

Cancer- related protein profile of patient-derived and commercial glioblastoma cell lines exposed to Temozolomide

“…Resident microglia and macrophages known as tumor-associated macrophages (TAMs) account for 30-50% of the tumor mass and with parallel low in ltration of functional T and NK cells build an immunosupressive GBM microenvironment [39]. Tumor resection stimulates microglia activation characterized by changes in morphology, polarization (M1, M2), gene expression, proliferation, phagocytic capacity, and migration towards the in icted injury [40]. Resection trigers also immediate and prolonged effects on the cytokine expression pro le.…”

Glioma-associated microglia/macrophages (GAMs) in glioblastoma: Immune function in the tumor microenvironment and implications for immunotherapy

“…For instance, glioma cells can secrete versican, which promotes the activation of microglia through the Toll-like receptor 2 (TLR2) signaling pathway ( 63 , 64 ). Some researchers even propose the hypothesis that the immune system does not recognize malignant tumor cells as invaders in the CNS, but rather helps them infiltrate and grow ( 65 ). These effects are largely due to the recruitment of microglia/macrophages by tumor cells.…”

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

“…It has not been long since it has been recognized that TAMs from GBMs have a monocyte origin besides microglial origin and that the recruitment of different types of monocytes from the bloodstream is closely related to the GBM microenvironment and its different areas, and the BBB does not necessarily have to be disrupted [ 52 , 53 ]. Monocytes are not a homogeneous population, but they rather vary in phenotype and function.…”

“…Human monocytes are commonly divided into three subsets based on CD14 and CD16 expression, and the recent incorporation of 6-sulfo LacNac (SLAN) expression allows a better differentiation between subtypes [ 53 ]: classical monocytes (CD14+ CD16− SLAN−), intermediate monocytes (CD14+ CD16+ SLAN−), and non-classical monocytes (CD14low/− CD16+ SLAN+) [ 55 ]. Classical monocytes, similar to those of mouse LY6C HI monocytes, highly express CCR2; they are the most prevalent monocyte subset in human blood, and they are recruited in inflamed environments [ 52 ].…”