Tumor-Associated Macrophages in Glioma: Friend or Foe?

Abstract

Tumor-associated macrophages (TAMs) contribute substantially to the tumor mass of gliomas and have been shown to play a major role in the creation of a tumor microenvironment that promotes tumor progression. Shortcomings of attempts at antiglioma immunotherapy may result from a failure to adequately address these effects. Emerging evidence supports an independent categorization of glioma TAMs as alternatively activated M2-type macrophages, in contrast to classically activated proinflammatory M1-type macrophages. These M2-type macrophages exert glioma-supportive effects through reduced anti-tumor functions, increased expression of immunosuppressive mediators, and nonimmune tumor promotion through expression of trophic and invasion-facilitating substances. Much of our work has demonstrated these features of glioma TAMs, and together with the supporting literature will be reviewed here. Additionally, the dynamics of glioma cell-TAM interaction over the course of tumor development remain poorly understood; our efforts to elucidate glioma cell-TAM dynamics are summarized. Finally, the molecular pathways which underlie M2-type TAM polarization and gene expression similarly require further investigation, and may present the most potent targets for immunotherapeutic intervention. Highlighting recent evidence implicating the transcription factor STAT3 in immunosuppressive tumorigenic glioma TAMs, we advocate for gene array-based approaches to identify yet unappreciated expression regulators and effector molecules important to M2-type glioma TAMs polarization and function within the glioma tumor microenvironment.

Perivascular niches as points of the utmost expression of tumor microenvironment

“…Most observations [25][26][27][28][29] are today in favor of an immunosuppressive, pro-tumor function of GAMs (30,31), despite some doubts exist [32]. GAMs increase with malignancy [15,[33][34][35], but only if RRM of lowgrade gliomas (LGG) or of infiltrating areas of GB are disregarded [36].…”

Targeting tumor-associated macrophages by anti-tumor Chinese materia medica

“…M1 M s participate in the Th1 in ammatory responses primarily through production of pro-inflammatory mediators and up-regulation of cell surface molecules necessary for antigen presentation to activate Th1 cells and enhance the ability to phagocytose pathogenic material. (19,20) M2-type M s, typically induced by Th2 cytokines, mediate resistance to parasites, mediate immune regulation and tissue repair. (4,21) M2 M s release high levels of IL-10 and low levels of IL-12 and IL-23.…”

“…Thus, CMM targeting TAMs may be considered as an additional anti-tumor therapy applicable to multiple stages of carcinogenesis. (19,32) Tumor Initiation…”

Breaking immunotolerance of tumors: A new perspective for dendritic cell therapy

“…In many cancer types, a correlation has been found between high TAM numbers and poor prognosis (Chen et al, 2011;Kennedy et al, 2013;Medrek et al, 2012;Piña et al, 2010). TAM resemble the so-called M2 population of macrophages stimulated by T H 2 cytokines in that they have scavenging activity, stimulate wound healing, and suppress T H 1 immune responses; this is in contrast to M1 macrophages, that are stimulated by bacterial products and T H 1 cytokines (like IFN) to enhance the host immune response (Allavena & Mantovani, 2012;Sica et al, 2012).…”