Brain Tumor Microenvironment and Host State: Implications for Immunotherapy

Abstract

Glioblastoma (GBM) is a highly lethal brain tumor with poor responses to immunotherapies that have been successful in more immunogenic cancers with less immunosuppressive tumor microenvironments (TME). The GBM TME is uniquely challenging to treat due to tumor cell-extrinsic components that are native to the brain, as well as tumor-intrinsic mechanisms that aid in immune evasion. Lowering the barrier of immunosuppression by targeting the genetically stable tumor stroma presents opportunities to treat the tumor in a way that circumvents the complications of targeting a constantly mutating tumor with tumor antigen-directed therapies. Tumor-associated monocytes, macrophages, and microglia are a stromal element of particular interest. Macrophages and monocytes compose the bulk of infiltrating immune cells and are considered to have protumor and immunosuppressive effects. Targeting these cells or other stromal elements is expected to convert what is considered the "cold" TME of GBM to a more "hot" TME phenotype. This conversion could increase the effectiveness of what have become conventional frontline immunotherapies in GBM-creating opportunities for better treatment through combination therapy.

Figure 1.. Tumor extrinsic mechanisms in Glioblastoma tumor microenvironment mediated by non-immune cells

Non-immune cells contribute to the immunosuppressive environment of the GBM TME in the following ways. 1. Although it is disrupted the blood brain barrier remains selectively permeable to both effector cells, and therapeutics. 2. Astrocytes are a source of pro-tumor factors which support the growth and metastatic capability of tumor cells. 3. Neurons support tumor cell proliferation via secretion of NLGN3. Redrawn from an illustration by Megan Llewellyn, MSMI, CMI; copyright Duke University; with permission under a CC-BY 4.0 license.

Figure 2.. Tumor extrinsic mechanisms in Glioblastoma tumor microenvironment mediated by immune cells

Infiltrating immune cells largely contribute to immunosuppression, or have their anti-tumor effector functions muted by exhaustion. A. NK cells have reduced cytotoxic capacity due to HLA-G expression on GBM cells. B. TAMs release pro-tumor factors which support tumor growth and suppress effector T cell function. C. T_Reg cells directly suppress CD8+ T cell cytotoxic capacity, and CD8+ and CD4+ T cells highly express exhaustion markers and are considered functionally exhausted. D. One potential method of increasing the immunogenicity of the GBM TME is by increasing trafficking to the tumor via forced expression of CD6 and VLA-4. Redrawn from an illustration by Megan Llewellyn, MSMI, CMI; copyright Duke University; with permission under a CC-BY 4.0 license.

Figure 3.. Tumor intrinsic mechanisms in Glioblastoma tumor microenvironment

Tumor intrinsic mechanisms present in GBM shown to modulate the TME and contribute to immunosuppression. The main pathways altered in GBM are the: A. Ras-Mitogen Activated Protein Kinase (Ras-MAPK); B. WNT/β-catenin (WNT); C. Phosphoinositide 3-kinase (PI3K); D. indoleamine 2 3-dioxygenase (IDO); E. Isocitrate Dehydrogenase-1 (m-IDH); and F. p53. Small molecule inhibitors targeting these pathways are currently in development for clinical application. Redrawn from an illustration by Megan Llewellyn, MSMI, CMI; copyright Duke University; with permission under a CC-BY 4.0 license.