- Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL - 60611, United States
- Faculty of Medicine, American University of Beirut, Riad El-Solh
- Department of Neurosurgery, Neuroscience Research Center, Faculty of Medical Sciences, Lebanese University, Beirut, Beyrouth - 1102 2801, Lebanon
DOI:10.25259/SNI-97-2019
Copyright: © 2019 Surgical Neurology International This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-Share Alike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.How to cite this article: Fares J, Fares MY, Fares Y. Natural killer cells in the brain tumor microenvironment: Defining a new era in neuro-oncology. Surg Neurol Int 26-Mar-2019;10:43
How to cite this URL: Fares J, Fares MY, Fares Y. Natural killer cells in the brain tumor microenvironment: Defining a new era in neuro-oncology. Surg Neurol Int 26-Mar-2019;10:43. Available from: http://surgicalneurologyint.com/surgicalint-articles/9241/
INTRODUCTION
Malignant brain tumors cultivate a variety of mechanisms to escape local and systemic immunity. Current treatments are restricted to neurosurgical procedures, chemotherapy, and radiotherapy.[
Brain tumor cells are equipped with the ability of secreting numerous chemokines, cytokines, and growth factors that stimulate the infiltration of various neural cells and a range of immune cells into the tumor. Altogether, these cells create a special niche called the tumor microenvironment, which is crucial for cancer proliferation, spread, and response to treatment. The tumor microenvironment has the ability of reprogramming attacking immune cells through local release of cytokines and chemokines,[
Natural killer (NK) cells are large granular lymphocytes that play an important role in antitumor immunity. On activation, NK cells induce target cell apoptosis through contact-dependent cytotoxicity primarily mediated by perforin and granzyme B[
NK CELLS AND THE BRAIN TUMOR MICROENVIRONMENT
NK cells constitute an integral part of the intratumoral immune cell population in the brain tumor microenvironment. Multiple studies have investigated NK cell numbers and activity in patients with brain tumors. Using suboptimal antibody techniques, Stevens et al.[
The functioning of NK cells is often affected in patients with brain tumors due to the immunosuppressive factors released by tumor cells. Glioma cells, for example, highly express a special form of major histocompatibility complex Class I molecules,[
Figure 1
Immune evasion mechanisms of brain tumors against natural killer (NK) cell surveillance and killing in the brain microenvironment. Tumor cells can secrete anti-inflammatory molecules (e.g., tumor necrosis factor-β) that bind and interact with NK cell receptors and eventually downregulate the frequency and cytotoxic activity of NK cells in the brain microenvironment. Tumor cells can also express ligands that bind to the inhibitory receptors of NK cells, which further downregulate their activity.
Impaired immune function and increased anti-inflammatory molecules are common in patients with glioma. In patients with glioblastoma multiforme, Fadul et al.[
NK CELL-BASED THERAPIES IN NEURO-ONCOLOGY
Although studies show that NK cells account for a minority of infiltrating leukocytes in brain tumors,[
NK cells may play an important role in antitumor immune responses in patients with various brain tumors. Castriconi et al.[
In pediatric brain tumors, it has been suggested that NK cells may also be effective against medulloblastoma. A phase 1 clinical trial is currently undergoing whereby autologous expanded NK cells are injected into the brain of patients who have undergone resection of recurrent infratentorial tumors (NCT02271711). Phase 2 clinical trials are employing expanded autologous NK cells in combination with T cells to attack high-risk pediatric brain tumors (NCT01804634 and NCT02100891). It is believed that combination therapies involving NK cells might enhance the effectiveness and/or overcome brain tumor immune escape mechanisms.[
While these early phase trials are vital to realize the optimal dose, safety, and efficacy of NK cell therapies, combination tactics are likely compulsory to fully reap the benefits of adoptive cell therapy. Potentiating the immunogenicity of the brain tumor microenvironment through immunotherapy may be necessary to fully exploit the effects of NK cell therapy.[
Although NK cell-based therapy exhibits limited neurological toxicity, it can produce immune reactions, such as graft versus host syndrome.[
CONCLUSION
In general, NK cells play an important role in antitumor immunity and have been shown to be present in brain tumor settings. Initial preclinical and clinical studies based on autologous NK cell therapies against brain tumors have shown some promise. Further trials and research are needed to elucidate more the mechanisms through which tumor cells evade NK cell-mediated surveillance and attacks. Combination strategies with immune checkpoint inhibitors may be effective in antagonizing the tumor-induced immunosuppression and increasing the functionality of the NK cells in the brain tumor settings, among other cancers. Investigating pure NK cell fractions and/or stimulating endogenous NK cells could ease the development of efficient and cost-effective therapeutic approaches that exploit NK cells as anticancer agents. Achieving clinical success with NK cells will get us one step closer from removing the “terminal illness” tag associated with many brain tumors.
Disclaimer
The views and opinions expressed in this article are those of the author and do not necessarily reflect the official policy or position of the Journal or its management.
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