Understanding the glioblastoma immune microenvironment as basis for the development of new immunotherapeutic strategies

Abstract

Cancer immunotherapy by immune checkpoint blockade has proven its great potential by saving the lives of a proportion of late stage patients with immunogenic tumor types. However, even in these sensitive tumor types, the majority of patients do not sufficiently respond to the therapy. Furthermore, other tumor types, including glioblastoma, remain largely refractory. The glioblastoma immune microenvironment is recognized as highly immunosuppressive, posing a major hurdle for inducing immune-mediated destruction of cancer cells. Scattered information is available about the presence and activity of immunosuppressive or immunostimulatory cell types in glioblastoma tumors, including tumor-associated macrophages, tumor-infiltrating dendritic cells and regulatory T cells. These cell types are heterogeneous at the level of ontogeny, spatial distribution and functionality within the tumor immune compartment, providing insight in the complex cellular and molecular interplay that determines the immune refractory state in glioblastoma. This knowledge may also yield next generation molecular targets for therapeutic intervention.

Analyzing One Cell at a TIME: Analysis of Myeloid Cell Contributions in the Tumor Immune Microenvironment

“…The resident immune system of the CNS, namely the microglia, are established contributors to CNS malignancies ( 146 ), but there are several other phagocytic myeloid cell populations in the CNS that are also, if not more so, implicated in a poor prognosis of the most aggressive form of CNS malignancy, glioblastoma multiforme (GBM). Perivascular, meningeal, and choroid plexus macrophages of the CNS have generally been overlooked as contributors to GBM ( 147 , 148 ), but the involvement of bone marrow-derived myeloid cells has recently been established, and even positively correlated, to poor outcomes in GBM models ( 116 , 149 ). As seen in the previous cancer studies, GBM TAMs co-express M1- and M2-associated markers, again making simple surface phenotyping of cells rather difficult, and creating the need for mechanism and pathway analysis ( 116 ).…”

“…A cohort of newly diagnosed patients in the study received standard-of-care adjuvant therapy ( 155 ), but the expansion of M-MDSCs were variable, indicating a potential difference in activation of myeloid cells following chemo- or radiotherapy ( 156 , 157 ). Additionally, a number of studies show increased peripheral MDSC counts in subsets of patients who received dexamethasone perioperatively, indicating a potential confounder, or contributor, in correlating overall survival with MDSC levels ( 118 , 148 , 149 ).…”

Immune profiling of gliomas reveals a connection with Tau function and the tumor vasculature

“…By contrast, recent clinical trials using programed cell death 1 (PD-1) antibodies in recurrent GBM has shown very few responses 2 , even though the ICI seems to reach the brain 3 . Compared to responsive cancers, gliomas harbor a lower burden of somatic mutations, fewer infiltrative T cells and a more immunosuppressive tumor microenvironment (TME) [4][5][6] . These factors could explain why glial tumors remain largely refractory to ICIs.…”

Immune profiling of gliomas reveals a connection with Tau function and the tumor vasculature.

“…By contrast, recent clinical trials using anti-programmed cell death 1 (PD-1) antibodies in recurrent GBM has shown very few responses [2], even though the ICIs seems to reach the brain [3]. Compared to responsive cancers, gliomas harbor a lower burden of somatic mutations, fewer in ltrative T cells and a more immunosuppressive tumor microenvironment (TME) [4][5][6]. These factors could explain why glial tumors remain largely refractory to ICIs.…”