Naoko Mise

Blockade of programmed death-1/programmed death ligand pathway enhances the antitumor immunity of human invariant natural killer T cells

The role of invariant natural killer T (iNKT) cells in antitumor immunity has been studied extensively, and clinical trials in patients with advanced cancer have revealed a prolonged survival in some cases. In recent years, humanized blocking antibodies against co-stimulatory molecules such as PD-1 have been developed. The enhancement of T cell function is reported to improve antitumor immunity, leading to positive clinical effects. However, there are limited data on the role of PD-1/programmed death ligand (PDL) molecules in human iNKT cells. In this study, we investigated the interaction between PD-1 on iNKT cells and PDL on antigen-presenting cells (APCs) in the context of iNKT cell stimulation. The blockade of PDL1 at the time of stimulation resulted in increased release of helper T cell (Th) 1 cytokines from iNKT cells, leading to the activation of NK cells. The direct antitumor function of iNKT cells was also enhanced after stimulation with anti-PDL1 antibody-treated APCs. According to these results, we conclude that the co-administration of anti-PDL1 antibody and alpha-galactosylceramide (αGalCer)-pulsed APCs enhances iNKT cell-mediated antitumor immunity.

Antibody-dependent cellular cytotoxicity toward neuroblastoma enhanced by activated invariant natural killer T cells

Anti‐ganglioside GD2 antibodies mainly work through antibody‐dependent cellular cytotoxicity (ADCC) and have demonstrated clinical benefit for children with neuroblastoma. However, high‐risk neuroblastoma still has a high recurrence rate. For further improvement in patient outcomes, ways to maximize the cytotoxic effects of anti‐GD2 therapies with minimal toxicity are required. Activated invariant natural killer T (iNKT) cells enhance both innate and type I acquired anti‐tumor immunity by producing several kinds of cytokines. In this report, we investigated the feasibility of combination therapy using iNKT cells and an anti‐GD2 antibody. Although some of the expanded iNKT cells expressed natural killer (NK) cell markers, including FcγR, iNKT cells were not directly associated with ADCC. When co‐cultured with activated iNKT cells, granzyme A, granzyme B and interferon gamma (IFNγ) production from NK cells were upregulated, and the cytotoxicity of NK cells treated with anti‐GD2 antibodies was increased. Not only cytokines produced by activated iNKT cells, but also NK‐NKT cell contact or NK cell‐dendritic cell contact contributed to the increase in NK cell cytotoxicity and further IFNγ production by iNKT cells and NK cells. In conclusion, iNKT cell‐based immunotherapy could be an appropriate candidate for anti‐GD2 antibody therapy for neuroblastoma.

Invariant natural killer T infiltration in neuroblastoma with favorable outcome

BackgroundTumor immunity has been suggested to play a key role in clinical and biological behavior of neuroblastomas. Given that CD1-restricted invariant natural killer T (iNKT) cells enhance both innate and acquired tumor immunity, we investigated the expression of the iNKT-cell-specific T-cell receptor Vα24-Jα18 in neuroblastoma tissues and its correlation with clinical and biological characteristics.MethodsUsing real- time quantitative PCR, we quantified the expression of Vα24-Jα18 in untreated tumor samples from 107 neuroblastoma cases followed in our institution and analyzed the correlation between the presence of infiltrated iNKT cells and clinical characteristics or patients’ outcome.ResultsVα24-Jα18 receptor was detected in 62 untreated cases (57.9%). The expression was significantly higher in stages 1, 2, 3, or 4S (P = 0.0099), in tumors with low or intermediate risk (P = 0.0050), with high TrkA expression (P = 0.0229), with favorable histology (P = 0.0026), with aneuploidy (P = 0.0348), and in younger patients (P = 0.0036). The overall survival rate was significantly higher in patients with iNKT-cell infiltration (log-rank; P = 0.0089).ConclusionsSince tumor-infiltrating iNKT cells were predominantly observed in neuroblastomas undergoing spontaneous differentiation and/or regression, we suggest that iNKT cells might play a key role in these processes.

Risk Factors for Intestinal Obstruction After Ladd Procedure.

Intestinal obstruction is a common complication after Ladd procedure. Ninety-three cases who had undergone the Ladd procedure between 1977 and 2013 treated at our own institution were retrospectively reviewed to identify the causes and risk factors for intestinal obstruction. The Ladd procedure has been performed without any intestinal fixing. Of the 87 cases who survived to discharge, intestinal obstruction was observed in 22 (25.3%). Among the cases with intestinal obstruction, 13 (59.1%) showed intestinal ischemia at the initial operation; this incidence was notably high, although it is low when only those cases with another concurrent surgical digestive disease are considered. All cases of intestinal obstruction were caused not by recurrent volvulus, but by adhesion between the intestine and the mesentery. Intestinal fixing is not required to prevent recurrent volvulus, but it is important to achieve adequate widening of the mesenteric base. The risk of intestinal obstruction after the Ladd procedure, on the other hand, is high. Moreover, patients with intestinal ischemia have an increased risk of intestinal obstruction.

Frequency and proliferative response of circulating invariant natural killer T cells in pediatric patients with malignant solid tumors

BackgroundInvariant natural killer T (iNKT) cells play an important role in tumor immunity, enhancing both innate and acquired immunity. We have previously shown the enhancement of antibody-dependent cellular cytotoxicity against neuroblastoma by activated iNKT cells. As a first step towards clinical application, we studied the frequency and proliferative response of circulating iNKT cells in children with and without cancer.MethodsBlood samples were collected from 10 patients with pediatric malignant solid tumors and 11 patients with non-neoplastic diseases (control). The frequency of circulating iNKT cells was quantified by flow cytometry. Whole peripheral blood mononuclear cells were then stimulated with α-galactosylceramide (α-GalCer) for 7 days, and the expansion rate of the iNKT-cell fraction was assessed.ResultsThe frequency of iNKT cells in the patients of the cancer and control group did not differ to a statistically significant extent. The iNKT-cell population increased after α-GalCer stimulation in all cases. The iNKT cells of patients who had undergone intensive chemotherapy also had the potential to expand in vitro.ConclusionsUnlike adult cancer patients, the numbers of circulating iNKT cells were not decreased in pediatric cancer patients. α-GalCer stimulation induced a proliferative response in all of the patients.

Hybrid video-assisted thoracoscopic surgery lobectomy of fissureless congenital cystic adenomatoid malformation: a case report

IntroductionThoracoscopic lobectomy for congenital pulmonary airway malformation has been indicated from the neonatal period to adolescence. However, it is difficult to approach the pulmonary artery for lobectomy in congenital lung malformations with incomplete or absent interlobar fissures. Multidetector computed tomographic images and computed tomography pulmonary angiography gave us helpful information before the operation. We performed thoracoscopic lobectomy for congenital pulmonary airway malformations with absent interlobar fissures and adhesions in accordance with information from multidetector computed tomographic images.Case presentationA 14-year-old Japanese girl received a diagnosis of congenital pulmonary airway malformation when she presented with pneumonia. Using multidetector computed tomography and three-dimensional reconstruction provides meticulous characterization of the anatomy in pediatric patients. We confirmed that her left A4+5 artery arose from her left pulmonary artery medial to A6. Her left pulmonary artery was divided just proximal to the A6 origin before the lobes were separated safely. We took advantage of using a stapler to divide the fissureless thick parenchyma. Perioperative diagnosis was congenital cystic adenomatoid malformation.ConclusionsWe used preoperative multidetector computed tomography to outline the bronchovascular anatomy and guide hybrid video-assisted thoracoscopic surgery for a congenital cystic adenomatoid malformation in a fissureless left lung.