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.

Keywords: cancer biology; glioblastoma; immunotherapy; microenvironment; regulatory T cell; tumor-associated dendritic cell; tumor-associated macrophage.

Figure 1.. Heterogeneity of the glioblastoma immune microenvironment and potential therapeutic targets.

Within glioblastoma tumors reside ontogenically distinct, immunoregulatory macrophages (Sall1⁺ tumor microglia, Sall1^- monocyte-derived macrophages), immunosuppressive Treg (eg CCR8⁺) and dysfunctional T-cell populations (CTLA-4/PD-1^hi). Not much is known about intratumoral DC subsets, although distinct DC populations are found in other brain regions, such as the dura mater (Van Hove et al., 2019). Glioblastoma also affects the phenotype of classical monocytes (Cl. Monocyte) in the periphery, which acquire an immunosuppressive (MDSC-like?) phenotype. Notably, the genetic make-up of the cancer cells (blue rectangle) and potentially also of the glioblastoma stem cells, affect the immune composition of the tumor, with for example a higher presence of lymphocytes in TCGA-MES tumors. Several potential therapeutic targets (CSF1R, SIRPa, CCR8, PD-1, CTLA-4), either already tested in the clinic or promising for the future, are highlighted.