Immune surveillance in glioblastoma: Role of the NKG2D system and novel cell‐based therapeutic approaches

Abstract

Glioblastoma, formerly known as glioblastoma multiforme (GBM), is the most frequent and most aggressive brain tumour in adults. The brain is an immunopriviledged organ, and the blood-brain barrier shields the brain from immune surveillance. In this review, we discuss the composition of the immunosuppressive tumour micromilieu and potential immune escape mechanisms in GBM. In this respect, we focus on the role of the NKG2D receptor/ligand system. NKG2D ligands are frequently expressed on GBM tumour cells and can activate NKG2Dexpressing killer cells including NK cells and γδ T cells. Soluble NKG2D ligands, however, contribute to tumour escape from immunological attack. We also discuss the current immunotherapeutic strategies to improve the survival of GBM patients. Such approaches include the modulation of the NKG2D receptor/ligand system, the application of checkpoint inhibitors, the adoptive transfer of ex vivo expanded and/or modified immune cells or the application of antibodies and antibody constructs to target cytotoxic effector cells in vivo. In view of the multitude of pursued strategies, there is hope for improved overall survival of GBM patients in the future. F I G U R E 1Treatment protocol of patients with newly diagnosed GBM. Radiochemotherapy (RCT) is applied according to the Stupps protocol following surgery (60 Gy splitted up on 2 Gy for 5 days a week in 6 cycles plus chemotherapy with temozolomide [TMZ] at 75 mg/ m 2 body surface during radiation). Following RCT, at least 6 cycles of chemotherapy with TMZ at a dose of 150-200 mg/m 2 body surface on 5 of 28 days are applied. Whenever applicable, tumour-treating fields (TTFs) are administered together with TMZ until reoccurrence of the disease How to cite this article: Chitadze G, Kabelitz D. Immune surveillance in glioblastoma: Role of the NKG2D system and novel cell-based therapeutic approaches.

Immunopathology of Extracellular Vesicles in Macrophage and Glioma Cross-Talk

“…Unfortunately, in tumors, the cancer often adapts to evade and manipulate the immune response. For example, tumors can begin to produce proteases, clipping off the ligand necessary for the macrophage-activated NK cells to attack the tumor cells [20]. Further, the tumor can signal directly to nearby macrophages to manipulate their activities, as discussed in detail in this review.…”

Evaluating glioblastoma tumour sphere growth and migration in interaction with astrocytes using 3D collagen-hyaluronic acid hydrogels

“…To identify differences resulting specifically from cross-talk as opposed to the presence of astrocytes alone, we also compared each GB co-culture to a sample comprised of mixed RNA from GB cells and astrocytes grown separately (Table 2 44,45,49,50,53,54,[58][59][60][61][62][63][64][65][66][67][68][69][70][71][72] ). Co-cultures vs. mixed separate culture comparisons for LN229 and U87 cells yielded 55 and 58 DEGs, respectively (Tables S4, S5 and Fig.…”

Drug resistance in glioblastoma: from chemo- to immunotherapy

“…The crosstalk between glioblastoma and the TME through which glioblastoma tumors escape immune surveillance is very complex and highly dynamic, involving many signaling mechanisms, including both soluble factors and cell-cell interactions. Besides the BBB, which prevents drugs from reaching their target sites, these mechanisms include various immune-suppressive mechanisms, such as secretion of immunosuppressive cytokines (IL-10, TGF-β, and IL-6) [ 104 , 105 ] , expression of immune checkpoints [ 106 ] , and recruitment of regulatory T cells (Tregs) [ 107 ] , induction of M2-like phenotype of tumor-associated MΦ and microglia [ 106 ] , reduced tumor antigen presentation through downregulation of MHC expression, and the ability to evade immune through soluble ligands [ 108 , 109 ] [ Figure 2 ].…”