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

Abstract

Gliomas are primary malignant brain tumors. These tumors seem to be more and more frequent, not only because of a true increase in their incidence, but also due to the increase in life expectancy of the general population. Among gliomas, malignant gliomas and more specifically glioblastomas (GBM) are a challenge in their diagnosis and treatment. There are few effective therapies for these tumors, and patients with GBM fare poorly, even after aggressive surgery, chemotherapy, and radiation. Over the last decade, it is now appreciated that these tumors are composed of numerous distinct tumoral and non-tumoral cell populations, which could each influence the overall tumor biology and response to therapies. Monocytes have been proved to actively participate in tumor growth, giving rise to the support of tumor-associated macrophages (TAMs). In GBM, TAMs represent up to one half of the tumor mass cells, including both infiltrating macrophages and resident brain microglia. Infiltrating macrophages/monocytes constituted ~ 85% of the total TAM population, they have immune functions, and they can release a wide array of growth factors and cytokines in response to those factors produced by tumor and non-tumor cells from the tumor microenvironment (TME). A brief review of the literature shows that this cell population has been increasingly studied in GBM TME to understand its role in tumor progression and therapeutic resistance. Through the knowledge of its biology and protumoral function, the development of therapeutic strategies that employ their recruitment as well as the modulation of their immunological phenotype, and even the eradication of the cell population, can be harnessed for therapeutic benefit. This revision aims to summarize GBM TME and localization in tumor niches with special focus on TAM population, its origin and functions in tumor progression and resistance to conventional and experimental GBM treatments. Moreover, recent advances on the development of TAM cell targeting and new cellular therapeutic strategies based on monocyte/macrophages recruitment to eradicate GBM are discussed as complementary therapeutics.

The prognostic value of tumor-associated macrophages in glioma patients

“…On the contrary, M2 has an anti-inflammatory and tumor progression promoter phenotype, which produces IL-10, VEGF and causes immunosuppression to promote tumor development. [ 44 ] Studies have shown that glioblastoma with a high proportion of monocyte has mesenchymal characteristics, increased angiogenesis, and poor prognosis. [ 45 ] Other studies have also shown that high expression of macrophage related genes predicts poor prognosis in glioma patients with mesenchymal subtypes.…”

The Role of Mesenchymal Reprogramming in Malignant Clonal Evolution and Intra-Tumoral Heterogeneity in Glioblastoma

“…Collectively, interactions between the immune components of TME and GBM cells enhance the adaptive fitness of tumor cells within the hypoxic niche through MES reprogramming ( Figure 2 ). Such interactions can provide valuable insights into the complex cellular and molecular interplay with the TME and may also yield innovative therapeutic targets [ 139 , 140 ].…”

The role of angiogenic growth factors in the immune microenvironment of glioma

“…Macrophages in gliomas were differentiated from VEGF producing monocytes. The number of macrophages was positively correlated with VEGF expression ( 50 ). Meanwhile, macrophages upregulate VEGFR1 expression and promote formation of GAMs ( 51 ).…”