|Year : 2019 | Volume
| Issue : 3 | Page : 133-138
Role of natural killer cells in isocitrate dehydrogenase 1/2 mutant glioma pathogenesis and emerging therapies
Xiaoran Zhang1, Aleksandra Safonova2, Aparna Rao1, Nduka Amankulor1
1 Department of Neurological Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
2 School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
|Date of Submission||20-Mar-2019|
|Date of Decision||12-Apr-2019|
|Date of Acceptance||07-May-2019|
|Date of Web Publication||26-Sep-2019|
Dr. Nduka Amankulor
Suite B400 Lothrop Street, Pittsburgh, PA 15213
Source of Support: None, Conflict of Interest: None
Gliomas are the most common primary central nervous system malignancy and have an overall poor prognosis, despite aggressive treatment. Understanding the immune microenvironment of these fatal tumors will advance discovery of immune-related therapeutic targets. Natural killer (NK) cells are innate lymphoid cells that constitute the first line of host-tumor immune responses since these cells do not require prior sensitization or tumor antigen recognition to kill. NK cells kill tumor cells by recognizing stress-induced ligands expressed on tumor cells, thereby providing an efficient path to early tumor cytolysis. Dysregulation of NK-mediated immunity plays a prominent role in immune escape for glioblastoma (World Health Organization Grade IV gliomas) and for various low-grade diffuse gliomas. Thus, the biology of NK cells is fertile ground for identifying novel immunotherapeutic targets in glioma. This review discusses the biology of NK cells as well as the potential applications for immunotherapy in the treatment of gliomas.
Keywords: Autologous cell transfer, glioblastoma, glioma, immune, immunotherapy, isocitrate dehydrogenase, microenvironment, natural killer cells
|How to cite this article:|
Zhang X, Safonova A, Rao A, Amankulor N. Role of natural killer cells in isocitrate dehydrogenase 1/2 mutant glioma pathogenesis and emerging therapies. Glioma 2019;2:133-8
|How to cite this URL:|
Zhang X, Safonova A, Rao A, Amankulor N. Role of natural killer cells in isocitrate dehydrogenase 1/2 mutant glioma pathogenesis and emerging therapies. Glioma [serial online] 2019 [cited 2020 Feb 19];2:133-8. Available from: http://www.jglioma.com/text.asp?2019/2/3/133/267914
| Introduction|| |
Treatment of glioma in adults remains a clinical challenge, with surgical resection followed by concurrent chemoradiation, the mainstay of treatment. However, this only offers prolonged survival without possibility of cure. Cancer immunotherapy is a therapeutic modality that augments inherent native immune responses to malignancies. There has been remarkable success with immunotherapy in a variety of cancers with agents that primarily target T-cell-mediated responses; however, far fewer immunotherapeutic strategies have focused on natural killer (NK) cells. NK cells constitute our first line of defense against neoplastic transformation and have the potential to become an integral component of glioma immunotherapy. In this review, we aim to illustrate the importance of NK cells in immunosurveillance against neoplasms, detail the mechanism by which isocitrate dehydrogenase (IDH)-mutant gliomas subvert NK-mediated immunosurveillance, and summarize the current literature on NK-based immunotherapy.
| Correlation of Immune Phenotypes With Genetic Alterations in Glioma|| |
Gliomas are central nervous system tumors comprised of neuroglial cells. They account for 27% of all adult brain tumors and 80% of malignant brain primary brain tumors in adults. The current annual incidence of gliomas is 6 per 100,000 in the US. They are classified on a grading system based on the World Health Organization criteria, with low-grade gliomas relating to a well-differentiated tumor as well as a better prognosis, while the higher grades, III and IV, relating to anaplastic tumors which have a worse prognosis. Glioblastomas (GBMs) are Grade IV gliomas, which represent approximately half of the glioma cases and are the most resistant to treatment. The current standard of care for the treatment of high-grade gliomas is resection of the tumor followed by concomitant chemoradiation therapy with temozolomide and external beam radiation. There are several factors which have a more favorable prognosis for the patients, such as younger age and higher Karnofsky performance score. Even in the most favorable circumstances, overall survival after diagnosis remains at a dismal 12–18 months. This grim prognosis necessitates new and innovative treatment strategies such as immunotherapy.
Regulation of the immune environment is associated with the genetic profile of the tumors. One of the most prevalent mutations in low-grade gliomas and secondary GBMs is the IDH mutation with IDH1/IDH2 mutations predominating in diffuse astrocytomas and oligodendroglial tumors. This mutation leads to a hypermethylated phenotype, also called glioma CpG island methylation phenotype, resulting in the silencing of numerous immune-regulatory genes.IDH-mutant gliomas are present in younger patients and confer improved, though ultimately dismal, survival outcomes compared to IDH wild-type GBM.IDH wild-type tumors are characterized by driver mutations in the telomerase reverse transcriptase gene (TERT) promoter with driver genetic alterations in the epidermal growth factor receptor, NF1. In spite of differing clinical outcomes, genetic alterations, and biology in gliomas, it is increasingly apparent that each unique driver mutation in glioma can confer distinct suppressive immune profiles. The mutation in isocitrate dehydrogenase results in the production of (R)-2-hydroxyglutarate (2-HG), a signature on co-metabolite of these tumors. 2-HG acts at the epigenetics to suppress the expression of multiple antitumor immune genes, thereby creating an immune-suppressive microenvironment to allow for the progression to a high-grade tumor. The IDH mutation occurs very early in the progression of gliomas and often coexists with other prevalent glioma mutations, including 1p/19q co-deletion and TERT promoter mutations. The 1p/19q co-deletion is a defining biomarker of oligodendrogliomas. The presence of co-deletion in patients is correlated with an improved chemosensitivity as well as recurrence-free survival. On the other hand, mutations in the TERT promoter gene are correlated with a worse prognosis. These are just several prominent mutations, and each subgroup determines the glioma microenvironment as well as the corresponding malignancy of the tumor.
The glioma microenvironment and overall immune phenotype of each individual patient can correlate with their clinical outcomes. A study compared 51 patients with GBM with 36 healthy volunteers and found distinct correlations in immune phenotypes between the patients and healthy individuals. However, when immune phenotypes were correlated with survival, a greater percentage of CD8-positive cytotoxic T-cells and activated NK cells was correlated with superior survival time, yet higher overall lymphocyte count was correlated with shorter survival. In a separate study, the immune microenvironment of IDH-mutant gliomas was found to contain fewer CD45+ cells compared to wild-type gliomas, suggesting a general reduction in the leukocyte population. In particular, macrophages, monocytes, and polymorphonuclear leukocytes were reduced in IDH-mutant gliomas. The mutant gliomas also contain reduced levels of leukocyte chemoattractants, including C-C motif chemokine ligand-2 and chemokine (C-X-C motif) ligand-2. Migration of neutrophils is impaired by factors in IDH-mutant gliomas as measured by transmigration assays. IDH-mutant tumors also exhibit a decrease in the proportion and overall number of cytotoxic (CD8) T-cells compared to IDH wild-type gliomas. In a series of elegant experiments, it was demonstrated that transcriptional silencing of STAT1 by 2-HG leads to downregulation of CD8 chemoattractive chemokines, chemokine (C-X-C motif) ligand-9 and chemokine (C-X-C motif) ligand-10. Notably, these studies contradict earlier studies that correlate NK and CD8 T-cell infiltration with survival, since patients with IDH-mutant gliomas demonstrate markedly longer survival than their IDH wild-type counterparts.
Another mechanism utilized by IDH-mutant gliomas to establish a suppressive immune microenvironment involves the downregulation of activating NK group 2D (NKG2D) ligands. Our group analyzed immune gene expression patterns in IDH-mutant and IDH wild-type diffuse gliomas and found a substantial reduction in the expression of genes mapping to the NKG2D locus at chromosome 6p21.3, adjacent to the major histocompatibility complex genes. Interestingly, IDH-mutant gliomas demonstrate wide hypermethylation of this chromosomal locus, thereby establishing a mechanism for suppressed expression. These NKG2D ligands, which include the UL-16 binding proteins 1–6 (ULBPs 1–6), encode for NK cell ligands, and their expressions are reduced in both IDH mutant astrocytes as well as primary glioma cell lines. The expression of two of these ligands, ULBP1 and ULBP3, exhibited a directly proportional relationship to NK-mediated toxicity, with a greater expression in IDH wild-type cells correlating with greater NK-mediated toxicity. On the other hand, IDH-mutant astrocytes were found to be more resistant to NK cells killing. In addition, NK cell activation, which is characterized by the secretion of interferon-gamma (IFN-γ), was also reduced in IDH-mutant tumors. Treatment with an NKG2D blocking antibody significantly reduced NK-mediated toxicity in wild-type cells, while not completely obliterating the response, suggesting that the interaction between NK cells and NKG2D ligands plays a significant role in NK-mediated toxicity but is not the only mechanism. In addition, treatment of IDH wild-type astrocytes with 2-HG, the characteristic oncometabolite of IDH-mutant gliomas, was sufficient to induce resistance to NK-mediated cytotoxicity, suggesting that 2-HG plays a major role in the methylation and subsequent silencing of the genes encoding for the NKG2D ligands. These findings underscore a possible mechanism for the immunosuppressive environment seen in IDH-mutant gliomas, as well as a plausible therapeutic strategy to improve immune recognition and NK cell-mediated toxicity of both IDH-mutant and wild-type gliomas. Immune evasion is necessary for malignant transformation; however, the mechanisms of immune escape can vary between different malignancies and the mechanism of immune escape is not the only determinant of disease severity. We believe that deficiencies in NK function represent a powerful node of immune escape in IDH-mutant gliomas  but acknowledge that IDH wild-type gliomas possess different (non-NK) mechanisms of immune escape in addition to powerful genomic alterations that drive higher rates of cellular proliferation and tumor invasiveness.
| Natural Killer Cells|| |
NK cells are innate immune lymphocytic cells notable for their cytotoxic activity and secretion of inflammatory cytokines against neoplastic and virally infected cells. In the 1970s, Herberman et al. identified a subset of lymphocytes with cytotoxic activity against neoplastic cells without prior sensitization which they subsequently named killer cells. NK cells can accurately distinguish between healthy self-cells and either neoplastic or virally infected nonself-cells without the need for prior antigen exposure, making it a component of the innate immune response. This is accomplished through the recognition of class I major histocompatibility complex molecules and stress ligands expressed on the surface of cells by a myriad of surface receptors. NK cells express both activating and inhibitory receptors, and the activity of NK cells is dependent on the summation of the receptors. NK-activating receptors recognize a wide variety of ligands that are expressed during times of cellular stress. NK inhibitory receptors such as the killer immunoglobulin receptor recognize the presence of major histocompatibility complex class I molecules which are expressed by normal cells but frequently suppressed in virally suppressed cells.,,
On activation, NK cells utilize several mechanisms of cytotoxicity [Figure 1]. One method is through the release of cytolytic granules containing perforin and granzyme B that are released into the target cell, leading to the formation of pores and degradation of target cellular membrane. NK cells can also express death receptor ligands such as the FasL or tumor necrosis factor-related apoptosis-inducing ligand, which can induce caspase-dependent apoptosis upon binding to death receptors on their target cells. Finally, NK cells express CD16, a low-affinity receptor for Fc portion of immunoglobulin G, allowing them to bind to antibody-coated cells to be destroyed through antibody-dependent cell cytotoxicity.
|Figure 1: Graphical overview of mechanisms of NK cell activation and cytotoxicity. Cytotoxicity is driven by interaction of activating receptors such as NKG2D, CD16 with its cognate ligands leading them to release of cytolytic enzymes including perforin, granzyme B, and pro-inflammatory cytokines. Binding of inhibitory receptors such as KIR and NKG2A with its cognate ligands leads to inhibition of cytotoxicity. NK cell expansion and activation are dependent on IL-2 and IL-15. NK: Natural killer, TNF-α: Tumor necrosis factor-alpha, IFN-γ: Interferon-gamma, IL: Interleukin, NKG2D: NK group 2D, MHC: Major histocompatibility complex, MICA/B: MHC class I polypeptide-related sequence A/B, ULBP1–2: UL-16 binding proteins 1–2, KIR: Killer immunoglobulin receptor, NKG2A: NK group 2A, HLA-E: Human leukocyte antigen class I histocompatibility antigen, alpha chain E|
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One of the best characterized activating receptors is the NKG2D receptor. This receptor recognizes at least six different NK cell ligands, including major histocompatibility complex class I polypeptide-related sequence A, major histocompatibility complex class I polypeptide-related sequence B, ULBP1, ULBP2, and ULBP3. Activation of this receptor activates phosphatidylinositol 3 kinase, leading to perforin-dependent cytotoxicity. These activating receptors are not present on normal tissue and are therefore not targeted by NK cells. During stress or infection of the tissue, this receptor is upregulated to allow for recognition by the NK cell and subsequent destruction. Data have shown that in certain cancers, the ligands for the NKG2D receptor are shed in the serum, leading to a reduction of the cytotoxic effects of NK cells.
Alterations in activating and inhibitory NK cell receptors have been reported in various cancers, suggesting tumor-induced changes leading to immune surveillance escape and tumor progression. NK cells in ovarian carcinoma were found to have reduced levels of activating receptors, including DNAX accessory molecule-1, 2B4, and CD16, while NK cells isolated from tongue cancer were found to have the increased level of an inhibitor receptor, NKG2A., In addition, the cytolytic activity of NK cells isolated from tumors was found to be lower than that of NK cells isolated from healthy tissue. NK cells in acute myeloid leukemia were found to express the tumor necrosis factor receptor CD137 when activated, which interacted with the CD137 ligand expressed on leukemic cells. This interaction affected the cytotoxicity of NK cells through decreased production of IFN-γ and release of interleukin (IL)-10 and tumor necrosis factor by the leukemic cells. Blocking the CD137 receptor was found to be sufficient to restore NK cell cytotoxicity. The changes in NK cell phenotype were not exclusive to tumor-infiltrating NK cells but also affected NK cells in the peripheral blood. Peripheral blood isolated from patients with metastatic melanoma showed a decrease in cytotoxic NK cells, phenotypically characterized as CD16brightCD56dim, with a simultaneous increase in noncytotoxic NK cells, characterized as CD16dimCD56bright., This was also accompanied by an overall increase in inhibitory receptors and decrease in activating receptors on NK cells. These trends correlated with decreased NK cell activity and decreased IFN-γ production.
Overall, the presence of lymphocytes in the tumor microenvironment, or tumor-infiltrating lymphocytes, has been shown to correlate with prolonged survival time in colorectal cancer, squamous cell lung cancer, and gastric carcinoma, with NK cells being an integral component of this population.,, Furthermore, severity of disease tends to inversely correlate with the prevalence of NK cells in the tumors. Advanced neoplasm cases with metastases contain a low prevalence of activated NK cells, compared to those with no metastases where there is a higher prevalence of NK cells. Above findings point out an integral role for NK cells in the progression neoplastic disease.
| Natural Killer Immunotherapy|| |
The ability to manipulate and use NK cells for immunotherapy is rapidly evolving, paralleling our understanding of the function and mechanism behind NK cell-mediated immunity. The first trial with the use of NK cells for immunotherapy involved the infusion of haploidentical NK cells into patients in combination with IL-2, a cytokine used for the expansion of NK cell populations, for the treatment of advanced cancer. However, this was proven ineffective due to the ability of IL-2 to also activate T-regulatory cells, which can lead to immunosuppression. Since then, more specific molecules and key NK cell pathways that can preferentially target NK cell differentiation and activation have been identified. These molecules include cytokines such as IL-15 and Toll-like receptor 3 and 9 agonists.
There are several key NK cell-mediated pathways that can be influenced pharmacologically. The balance of inhibitory and activating receptors on NK cells can be altered to potentiate the stimulatory signals. This is accomplished through the use of antibodies directed against inhibitory killer immunoglobulin receptor receptors, which has been shown to promote tumor rejection. Killer immunoglobulin receptor ligand compatibility was the only independent factor found to influence a poor graft-versus-host outcome in patients receiving transplants for acute leukemia. Activation of the stimulatory receptors such as NKG2D has also been shown to induce NK cell activity as discussed above. In addition, activation of the NK cell-dependent antibody-dependent cell-mediated cytotoxicity pathway can be induced through the use of cytokines (IL-2) and monoclonal antibodies (rituximab). NK cells mediate antibody-dependent cell-mediated cytotoxicity through binding of their FCγ receptors to immunoglobulin G bound to tumor cells. Interestingly, polymorphisms in the Fcγ region of NK cells have been found in lymphomas and predict the response of the tumor cells to monoclonal therapies. Finally, dendritic cell-derived exosomes are being explored as vaccines to potentiate the NK cell response. In a Phase I trial, NK cell activity was restored through dendritic cell-derived exosomes in seven out of 15 patients diagnosed with Stage IV melanoma. Through dendritic cell secretion of IL-12, NK cells are induced to produce IFN-γ leading to increased cytolytic activity. IL-12 and IFN-γ also activate CD8+ T cells, which involves long-term immunity through activation of the adaptive immune response.
Potential therapy utilizing NK cells for the treatment of gliomas is currently under investigation, with most studies in the preclinical phases. Treatment of IDH-mutant cells with decitabine, a DNA methyltransferase 1 inhibitor which reverses methylation, can restore expression of NKG2D ligand expression (unpublished data). The therapeutic effects were sustained for up to 7 days in both IDH wild-type and IDH-mutant cell lines, with a much greater effect seen in the IDH-mutant cells. Treatment with decitabine increased the susceptibility of IDH-mutant astrocytes and glioma cell lines to NK cell-mediated cytotoxicity compared to the IDH-mutant control group treated with dimethyl sulfoxide. N6-isopentenyladenosine has been found to be another regulator of the expression of NKG2D ligands. Treatment of U343-MG GBM cells with N6-isopentenyladenosine activates p53, which in turn upregulates expression of NKG2D ligands. This increases killing and IFN-γ secretion by NK cells compared to the untreated cells. The KLRC3 gene, a gene encoding for NKG2E, is a gene found to be overexpressed in GBM. While the role of NKG2E has not yet been elucidated, NKG2E promotes immunosuppression and immune escape of gliomas. KLRC3 silencing enhanced apoptosis of U87-MG GBM cellsin vitro as well as inhibited tumor growth in xenografts in nude mice. Exosomes from NK cells were isolated to evaluate the cytotoxicity in both U87/MG/F cells andin vivo xenograft mouse models. Thein vitro cytotoxicity was confirmed with a cytotoxicity assay, while inhibition of tumor growth was seen in the xenograft mouse model. The function of myeloid-derived suppressor cells in conjunction with NK cells was assessed in galectin 1-deficient gliomas. Immunodepleted recombination activating gene 1−/− mice were conducive to the growth of the glioma, despite the presence of NK cells. However, the recruitment of myeloid-derived suppressor cells resulted in clearance of the tumor, emphasizing the importance of the myeloid-derived suppressor cells for NK cell activity. Finally, chimeric antigen receptor-engineering NK cells targeting the epidermal growth factor receptor in GBM demonstrated potent cytolytic activity against GBM cells through increased production of IFN-γ. Intracranial injections into the mouse models of GBM showed inhibition of tumor growth and increased survival time in mice.
A clinical study by Ishikawa et al. utilized NK cells by injecting ex vivo expanded NK cells cocultured with IL-2 into nine patients with GBM to assess safety and efficacy. Peripheral blood mononuclear cells obtained from the peripheral blood of each patient were obtained and added to an irradiated human feeder cell line. Human feeder cell line, a type of tumor with no surface antigens, was found to selectively induce NK cell expansion. Cells were cultured for 14 days, and subpopulation of NK cells was confirmed using flow cytometry. The cells were then injected into each patient both intravenously as well as into the tumor cavities three times per week for 4–5 weeks. This was accompanied by a dose of IL-2 along with IFN-β, due to its promotion of NK cell-mediated cytotoxicity. The results showed that injection of ex vivo expanded NK cells was safe and resulted in partial inhibition and reduction in tumor growth in two out of nine patients. In addition, the reduction in tumor volume was stabilized for more than 4 weeks.
Herein, we have reviewed the mechanisms behind NK cell activity as well as the pathogenesis of IDH-mutant gliomas. While there have been significant advances in the discovery and utilization of NK cells in recent years, future research will hopefully elucidate the mechanism behind successful activation of NK cells as well as combinatory approaches to target IDH-mutant gliomas.
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