Natural killer cell awakening: unleash cancer-immunity cycle against glioblastoma

Abstract

Due to the negligence of the complex tumor immune microenvironment, traditional treatment for glioblastoma has reached its limitation and cannot achieve a satisfying outcome in the past decade. The emergence of immunotherapy based on the theory of cancer-immunity cycle has brought a new dawn to glioblastoma patients. However, the results of most phase II and phase III clinical trials are not optimistic due to the simple focus on T cells activation rather than other immune cells involved in anti-tumor immunity. NK cells play a critical role in both innate and adaptive immunity, having the ability to coordinate immune response in inflammation, autoimmune disease and cancer. They are expected to cooperate with T cells to maximize the anti-tumor immune effect and have great potential in treating glioblastoma. Here, we describe the traditional treatment methods and current immunotherapy strategies for glioblastoma. Then, we list a microenvironment map and discuss the reasons for glioblastoma inhibitory immunity from multiple perspectives. More importantly, we focus on the advantages of NK cells as potential immune regulatory cells and the ways to maximize their anti-tumor immune effect. Finally, our outlook on the directions and potential applications of NK cell-based therapy combining with the advance technologies is presented. This review depicts NK cell awakening as the precondition to unleash the cancer-immunity cycle against glioblastoma and elaborate this idea from biology to clinical treatment.

Immunopotentiating Activity of Fucoidans and Relevance to Cancer Immunotherapy

“…The broad range of cytokines (e.g., IFN- , perforin, granzyme B) [ 127 , 130 , 145 ], and activating (e.g., NKp30, FasL) and inhibitory receptors (e.g., killer inhibitory receptor, KIR) located on the cell surface [ 145 , 146 ] allow them to interact with other immune cells or biomolecules which allow them to recognize tumor cells and then induce antitumor effects [ 145 , 147 ]. Furthermore, NK cells have also been described as DC promoters and T cell response regulators [ 147 ], suggesting that NK cells can enhance and maximize the antitumor effects of other immune cells in TME [ 145 ]. Ale et al showed that intraperitoneally administered fucoidan ( Fucus vesiculosus , 50 mg/kg) increased NK cell proliferation in C57BL/6 mice [ 129 ].…”

Investigating the Effects of Olaparib on the Susceptibility of Glioblastoma Multiforme Tumour Cells to Natural Killer Cell-Mediated Responses

“…NK cells and their diverse array of surface receptors hold a crucial role in cancer immunosurveillance and the expression of such NKRs and their corresponding ligands on tumour cells is critical to the successful eradication of GBM [ 47 , 48 , 49 , 50 , 51 ]. NK cell immunotherapy is a novel intervention that has demonstrated great potential for success in GBM, a malignancy with dismal survival rates and no curative treatment options [ 52 , 53 ]. The efficacy of adoptively transferred NK cells has been demonstrated in a variety of different cancers, including GBM [ 54 , 55 ].…”

“…The solid TME is an overall immunosuppressive environment primed to dampen and dysregulate the functionality of NK cells [ 16 , 28 , 52 , 71 , 72 ]. Hypoxia, nutrient deprivation, and the acidic pH coupled with NKR ligand shedding and the overabundance of immunosuppressive cytokines, such as TGF-β and PGE2, make the GBM TME a hostile environment for NK cells [ 16 , 28 , 71 , 73 ].…”

Exosomes‐mediated crosstalk between glioma and immune cells in the tumor microenvironment

“…NK cells represent a significant subset of lymphocytes in innate immunity. They enhance cytotoxicity in the immune response by releasing various cytokines, including perforin, interferon‐γ (IFN‐γ), tumor necrosis factor (TNF), granulocyte‐macrophage colony‐stimulating factor (GM‐CSF), and macrophage inflammatory protein‐1 (MIP‐1) 111,112 . Interleukin‐15 (IL‐15) significantly increases the potential of NK cell‐derived exosomes (NK‐Exo) for immunotherapy.…”