Regulation of Tumor Immunity by Tumor/Dendritic Cell Fusions

The goal of cancer vaccines is to induce antitumor immunity that ultimately will reduce tumor burden in tumor environment. Several strategies involving dendritic cells- (DCs)- based vaccine incorporating different tumor-associated antigens to induce antitumor immune responses against tumors have been tested in clinical trials worldwide. Although DCs-based vaccine such as fusions of whole tumor cells and DCs has been proven to be clinically safe and is efficient to enhance antitumor immune responses for inducing effective immune response and for breaking T-cell tolerance to tumor-associated antigens (TAAs), only a limited success has occurred in clinical trials. This paper reviews tumor immune escape and current strategies employed in the field of tumor/DC fusions vaccine aimed at enhancing activation of TAAs-specific cytotoxic T cells in tumor microenvironment.Foundation for the Promotion of Cancer Research; Mitsui Life Social Welfare Foundation; Grants-in-Aid for Scientific Research from the Ministry of Education, Cultures, Sports, Science, and Technology of Japan; Grant-in-Aid of the Japan Medical Association; Takeda Science Foundation; Pancreas Research Foundation of Japa

Immunologic Monitoring of Cellular Responses by Dendritic/Tumor Cell Fusion Vaccines

Although dendritic cell (DC)- based cancer vaccines induce effective antitumor activities in murine models, only limited therapeutic results have been obtained in clinical trials. As cancer vaccines induce antitumor activities by eliciting or modifying immune responses in patients with cancer, the Response Evaluation Criteria in Solid Tumors (RECIST) and WHO criteria, designed to detect early effects of cytotoxic chemotherapy in solid tumors, may not provide a complete assessment of cancer vaccines. The problem may, in part, be resolved by carrying out immunologic cellular monitoring, which is one prerequisite for rational development of cancer vaccines. In this review, we will discuss immunologic monitoring of cellular responses for the evaluation of cancer vaccines including fusions of DC and whole tumor cell

In vitro generation of cytotoxic and regulatory T cells by fusions of human dendritic cells and hepatocellular carcinoma cells

<p>Abstract</p> <p>Background</p> <p>Human hepatocellular carcinoma (HCC) cells express WT1 and/or carcinoembryonic antigen (CEA) as potential targets for the induction of antitumor immunity. In this study, generation of cytotoxic T lymphocytes (CTL) and regulatory T cells (Treg) by fusions of dendritic cells (DCs) and HCC cells was examined.</p> <p>Methods</p> <p>HCC cells were fused to DCs either from healthy donors or the HCC patient and investigated whether supernatants derived from the HCC cell culture (HCCsp) influenced on the function of DCs/HCC fusion cells (FCs) and generation of CTL and Treg.</p> <p>Results</p> <p>FCs coexpressed the HCC cells-derived WT1 and CEA antigens and DCs-derived MHC class II and costimulatory molecules. In addition, FCs were effective in activating CD4⁺and CD8⁺T cells able to produce IFN-γ and inducing cytolysis of autologous tumor or semiallogeneic targets by a MHC class I-restricted mechanism. However, HCCsp induced functional impairment of DCs as demonstrated by the down-regulation of MHC class I and II, CD80, CD86, and CD83 molecules. Moreover, the HCCsp-exposed DCs failed to undergo full maturation upon stimulation with the Toll-like receptor 4 agonist penicillin-inactivated <it>Streptococcus pyogenes</it>. Interestingly, fusions of immature DCs generated in the presence of HCCsp and allogeneic HCC cells promoted the generation of CD4⁺CD25^highFoxp3⁺Treg and inhibited CTL induction in the presence of HCCsp. Importantly, up-regulation of MHC class II, CD80, and CD83 on DCs was observed in the patient with advanced HCC after vaccination with autologous FCs. In addition, the FCs induced WT1- and CEA-specific CTL that were able to produce high levels of IFN-γ.</p> <p>Conclusion</p> <p>The current study is one of the first demonstrating the induction of antigen-specific CTL and the generation of Treg by fusions of DCs and HCC cells. The local tumor-related factors may favor the generation of Treg through the inhibition of DCs maturation; however, fusion cell vaccination results in recovery of the DCs function and induction of antigen-specific CTL responses in vitro. The present study may shed new light about the mechanisms responsible for the generation of CTL and Treg by FCs.</p

Safety of uterine fundal pressure maneuver during second stage of labor in a tertiary perinatal medical center: A retrospective observational study

Objective: This study aimed to evaluate the conformity of the indications and implementation status of uterine fundal pressure maneuver (UPFM) and to examine its safety according to the Japan Society of Obstetrics and Gynecology (JSOG) guidelines. Materials and methods: We selected all the patients (n = 265) who were treated with UFPM between January 2015 and March 2017. We first evaluated the conformity of the indications and implementation status of UFPM concerning the guidelines for obstetrical practice in Japan, 2017. Second, we retrospectively examined maternal and fetal adverse events (AEs) to determine the safety of UFPM. Results: In total, 265 patients underwent UFPM; of all the UFPM-assisted deliveries, 189 patients (72%) were evaluated for conformity. Of these 189 patients, 181 (95.7%) were confirmed to be compliant. Laceration of the birth canal was the most frequently occurring maternal AE, followed by cervical laceration. No cases of uterine rupture, severe AEs leading to an extended hospital stay, and maternal deaths were observed. Although fetal AEs requiring admission to neonatal intensive care unit (NICU) were recorded for 33 patients (12.5%), all newborns developed normally without sequela. Conclusion: The findings of this study may support the validity of the 2017 guidelines. Because it is difficult to find evidence of the safety of use of UFPM, it is essential to accumulate experiences and results learned in clinical practice to build a consensus in the future using the current 2017 guidelines as a standard as done in the current study. Keywords: Kristeller maneuver, Maternal outcome, Neonatal outcome, The second stage of labor, Uterine fundal pressur

Additional file 1: Figure S1. of Up-regulation of HER2 by gemcitabine enhances the antitumor effect of combined gemcitabine and trastuzumab emtansine treatment on pancreatic ductal adenocarcinoma cells

HER2 mRNA levels of GEM-treated MIA PaCa-2 cells did not increase at each time point. GEM-treated MIA PaCa-2 cells (0, 100, 300 and 1000 ng/ml, 2 h) were incubated for 2, 6, 12, 24 and 48 h, and their HER2 mRNA levels were determined using qRT-PCR. HER2 mRNA expression levels were normalized to that of 18S ribosomal RNA and quantified using the ΔΔCt method. (PPTX 83 kb