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NK cells with KIR2DS2 immunogenotype have a functional activation advantage to efficiently kill glioblastoma and prolong animal survival.

ABSTRACT: Glioblastomas (GBMs) are lethal brain cancers that are resistant to current therapies. We investigated the cytotoxicity of human allogeneic NK cells against patient-derived GBM in vitro and in vivo, as well as mechanisms mediating their efficacy. We demonstrate that KIR2DS2 immunogenotype NK cells were more potent killers, notwithstanding the absence of inhibitory killer Ig-like receptor (KIR)-HLA ligand mismatch. FACS-sorted and enriched KIR2DS2(+) NK cell subpopulations retained significantly high levels of CD69 and CD16 when in contact with GBM cells at a 1:1 ratio and highly expressed CD107a and secreted more soluble CD137 and granzyme A. In contrast, KIR2DS2(-) immunogenotype donor NK cells were less cytotoxic against GBM and K562, and, similar to FACS-sorted or gated KIR2DS2(-) NK cells, significantly diminished CD16, CD107a, granzyme A, and CD69 when in contact with GBM cells. Furthermore, NK cell-mediated GBM killing in vitro depended upon the expression of ligands for the activating receptor NKG2D and was partially abrogated by Ab blockade. Treatment of GBM xenografts in NOD/SCID mice with NK cells from a KIR2DS2(+) donor lacking inhibitory KIR-HLA ligand mismatch significantly prolonged the median survival to 163 d compared with vehicle controls (log-rank test, p = 0.0001), in contrast to 117.5 d (log-rank test, p = 0.0005) for NK cells with several inhibitory KIR-HLA ligand mismatches but lacking KIR2DS2 genotype. Significantly more CD56(+)CD16(+) NK cells from a KIR2DS2(+) donor survived in nontumor-bearing brains 3 wk after infusion compared with KIR2DS2(-) NK cells, independent of their proliferative capacity. In conclusion, KIR2DS2 identifies potent alloreactive NK cells against GBM that are mediated by commensurate, but dominant, activating signals.

SUBMITTER: Gras Navarro A

PROVIDER: S-EPMC4259203 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature

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NK cells with KIR2DS2 immunogenotype have a functional activation advantage to efficiently kill glioblastoma and prolong animal survival.

Gras Navarro Andrea A Kmiecik Justyna J Leiss Lina L Zelkowski Mateusz M Engelsen Agnete A Bruserud Øystein Ø Zimmer Jacques J Enger Per Øyvind PØ Chekenya Martha M

Journal of immunology (Baltimore, Md. : 1950) 20141107 12

Glioblastomas (GBMs) are lethal brain cancers that are resistant to current therapies. We investigated the cytotoxicity of human allogeneic NK cells against patient-derived GBM in vitro and in vivo, as well as mechanisms mediating their efficacy. We demonstrate that KIR2DS2 immunogenotype NK cells were more potent killers, notwithstanding the absence of inhibitory killer Ig-like receptor (KIR)-HLA ligand mismatch. FACS-sorted and enriched KIR2DS2(+) NK cell subpopulations retained significantly ...[more]

PMID: 25381437

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Project description:Glioblastoma (GBM) is the most malignant brain tumor where patients' survival is only 14.6 months, despite multimodal therapy with debulking surgery, concurrent chemotherapy and radiotherapy. There is an urgent, unmet need for novel, effective therapeutic strategies for this devastating disease. Although several immunotherapies are under development for the treatment of GBM patients, the use of natural killer (NK) cells is still marginal despite this being a promising approach to treat cancer. In regard of our knowledge on the role of NG2/CSPG4 in promoting GBM aggressiveness we investigated the potential of an innovative immunotherapeutic strategy combining mAb9.2.27 against NG2/CSPG4 and NK cells in preclinical animal models of GBM. Multiple immune escape mechanisms maintain the tumor microenvironment in an anti-inflammatory state to promote tumor growth, however, the distinct roles of resident microglia versus recruited macrophages is not elucidated. We hypothesized that exploiting the cytokine release capabilities of activated (NK) cells to reverse the anti-inflammatory axis combined with mAb9.2.27 targeting the NG2/CSPG4 may favor tumor destruction by editing pro-GBM immune responses. Combination treatment with NK+mAb9.2.27 diminished tumor growth that was associated with reduced tumor proliferation, increased cellular apoptosis and prolonged survival compared to vehicle and monotherapy controls. The therapeutic efficacy was mediated by recruitment of CCR2low macrophages into the tumor microenvironment, increased ED1 and MHC class II expression on microglia that might render them competent for GBM antigen presentation, as well as elevated IFN-? and TNF-? levels in the cerebrospinal fluid compared to controls. Depletion of systemic macrophages by liposome-encapsulated clodronate decreased the CCR2low macrophages recruited to the brain and abolished the beneficial outcomes. Moreover, mAb9.2.27 reversed tumor-promoting effects of patient-derived tumor-associated macrophage/microglia(TAM) ex vivo.Taken together, these findings indicate thatNK+mAb9.2.27 treatment may be an amenable therapeutic strategy to treat NG2/CSPG4 expressing GBMs. We provide a novel conceptual approach of combination immunotherapy for glioblastoma. The results traverse beyond the elucidation of NG2/CSPG4 as a therapeutic target, but demonstrate a proof of concept that this antibody may hold potential for the treatment of GBM by activation of tumor infiltrated microglia/macrophages.

Project description:The importance of maximal resection in the treatment of glioblastoma (GBM) has been reported in many studies, but maximal resection of thalamic GBM is rarely attempted due to high rate of morbidity and mortality. The purpose of this study was to investigate the role of surgical resection in adult thalamic glioblastoma (GBM) treatment and to identify the surgical technique of maximal safety resection. In case of suspected thalamic GBM, surgical resection is the treatment of choice in our hospital. Biopsy was considered when there was ventricle wall enhancement or multiple enhancement lesion in a distant location. Navigation magnetic resonance imaging, diffuse tensor tractography imaging, tailed bullets, and intraoperative computed tomography and neurophysiologic monitoring (transcranial motor evoked potential and direct subcortical stimulation) were used in all surgical resection cases. The surgical approach was selected on the basis of the location of the tumor epicenter and the adjacent corticospinal tract. Among the 42 patients, 19 and 23 patients underwent surgical resection and biopsy, respectively, according to treatment strategy criteria. As a result, the surgical resection group exhibited a good response with overall survival (OS) (median: 676 days, p < 0.001) and progression-free survival (PFS) (median: 328 days, p < 0.001) compared with each biopsy groups (doctor selecting biopsy group, median OS: 240 days and median PFS: 134 days; patient selecting biopsy group, median OS: 212 days and median PFS: 118 days). The surgical resection groups displayed a better prognosis compared to that of the biopsy groups for both the O6-methylguanine-DNA methyltransferase unmethylated (log-rank p = 0.0035) or methylated groups (log-rank p = 0.021). Surgical resection was significantly associated with better prognosis (hazard ratio: 0.214, p = 0.006). In case of thalamic GBM without ventricle wall-enhancing lesion or multiple lesions, maximal surgical resection above 80% showed good clinical outcomes with prolonged the overall survival compared to biopsy. It is helpful to use adjuvant surgical techniques of checking intraoperative changes and select the appropriate surgical approach for reducing the surgical morbidity.

Dataset Information

NK cells with KIR2DS2 immunogenotype have a functional activation advantage to efficiently kill glioblastoma and prolong animal survival.

Publications

NK cells with KIR2DS2 immunogenotype have a functional activation advantage to efficiently kill glioblastoma and prolong animal survival.

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