Heat Shock Proteins: Conditional Mediators of Inflammation in Tumor Immunity

Heat shock protein (HSP)-based anticancer vaccines have undergone successful preclinical testing and are now entering clinical trial. Questions still remain, however regarding the immunological properties of HSPs. It is now accepted that many of the HSPs participate in tumor immunity, at least in part by chaperoning tumor antigenic peptides, introducing them into antigen presenting cells such as dendritic cells (DC) that display the antigens on MHC class I molecules on the cell surface and stimulate cytotoxic lymphocytes (CTL). However, in order for activated CD8+ T cells to function as effective CTL and kill tumor cells, additional signals must be induced to obtain a sturdy CTL response. These include the expression of co-stimulatory molecules on the DC surface and inflammatory events that can induce immunogenic cytokine cascades. That such events occur is indicated by the ability of Hsp70 vaccines to induce antitumor immunity and overcome tolerance to tumor antigens such as mucin1. Secondary activation of CTL can be induced by inflammatory signaling through Toll-like receptors and/or by interaction of antigen-activated T helper cells with the APC. We will discuss the role of the inflammatory properties of HSPs in tumor immunity and the potential role of HSPs in activating T helper cells and DC licensing

Antigen-Specific Polyclonal Cytotoxic T Lymphocytes Induced by Fusions of Dendritic Cells and Tumor Cells

The aim of cancer vaccines is induction of tumor-specific cytotoxic T lymphocytes (CTLs) that can reduce the tumor mass. Dendritic cells (DCs) are potent antigen-presenting cells and play a central role in the initiation and regulation of primary immune responses. Thus, DCs-based vaccination represents a potentially powerful strategy for induction of antigen-specific CTLs. Fusions of DCs and whole tumor cells represent an alternative approach to deliver, process, and subsequently present a broad spectrum of antigens, including those known and unidentified, in the context of costimulatory molecules. Once DCs/tumor fusions have been infused back into patient, they migrate to secondary lymphoid organs, where the generation of antigen-specific polyclonal CTL responses occurs. We will discuss perspectives for future development of DCs/tumor fusions for CTL induction.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 Japan, The Promotion and Mutual Aid Corporation for Private School of Japan and Foundation for Promotion of Cancer Researc

The Role of Heat Shock Proteins in Antigen Cross Presentation

Heat shock proteins (HSPs) are molecular chaperones that bind tumor antigens and mediate their uptake into antigen presenting cells. HSP–antigen complexes are then directed toward either the MHC class I pathway through antigen cross presentation or the conventional class II pathway, leading to activation of T cell subsets. Uptake of HSP-chaperoned polypeptides can involve both receptor-mediated and receptor-independent routes, and mechanisms of antigen sorting between the Class I and II pathways after uptake are currently under investigation. The processes involved in internalization of HSP–antigen complexes differ somewhat from the mechanisms previously determined for (unchaperoned) particulate and free soluble antigens. A number of studies show that HSP-facilitated antigen cross presentation requires uptake of the complexes by scavenger receptors (SR) followed by processing in the proteasome, and loading onto MHC class I molecules. In this review we have examined the roles of HSPs and SR in antigen uptake, sorting, processing, cell signaling, and activation of innate and adaptive immunity

Strong plasmonic confinement and optical force in phosphorene pairs

The plasmonic responses in the spatially separated phosphorene (single-layer black phosphorus) pairs are investigated, mainly containing the field enhancement, light confinement, and optical force. It is found that the strong anisotropic dispersion of black phosphorus gives rise to the direction-dependent symmetric and anti-symmetric plasmonic modes. Our results demonstrate that the symmetrical modes possess stronger field enhancement, higher light confinement, and larger optical force than the anti-symmetric modes in the nanoscale structures. Especially, the light confinement ratio and optical force for the symmetric mode along the armchair direction of black phosphorus can reach as high as >90% and >3000 pN/mW, respectively. These results may open a new door for the light manipulation at nanoscale and the design of black phosphorus based photonic devices

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

Isolation and analysis of a very virulent Marek’s disease virus strain in China

BACKGROUND: A severe MD was broken out at a farm in Shandong, China, despite FC126 vaccination of the chickens at 1-day-old. The mortality of the flocks reached up to 38.3%. The infected chickens were found to have MD pathological changes, including enlargement of spleens, livers and kidneys, and tumors occured on organs later. Samples were collected from the chickens for diagnosis. METHODS: The collected samples were inoculated into primary duck embryo fibroblast (DEF) cells, and the MDV strain named SD2012-1 was isolated. In order to identify the isolate, amplification by PCR and sequencing of oncogenic Meq and vIL-8 gene were processed, the obtained sequences were compared with the sequences of reference strains, and SD2012-1 was used to challenge immunized SPF chickens. RESULTS: A very virulent MDV isolate strain, SD2012-1, was isolated from a chicken flock in Shandong Province, China, the isolate had the characteristics of very virulent MDV-1, nucleotide and deduced amino acid sequence comparisons of Meq and vIL-8 gene of SD2012-1 with those of reference strains showed SD2012-1 had high homology with MDV strains isolated from China, SD2012-1 could break through the protection provided by HVT vaccine and HVT + SB-1 vaccine immunization and caused the mortality of SPF chickens over 60%. The immune failure occured at the farm could be due to the improper selection of vaccines. SD2012-1 produced death later and the gross postmortem lesions of chickens died early and later were different. CONCLUSIONS: MDV strain SD2012-1 isolated from Shandong Province, China was found to have the characteristics of very virulent MDV-1, which could break through the protection provided by HVT vaccine and HVT + SB-1 vaccine, the virus seemed to have a long latent period, and cause different gross postmortem lesions of chickens between chickens died early and later. A better immunization way should be chosen to prevent infection of this MDV strain in field

Metastasis is an Early Event in Mouse Mammary Carcinomas and is Associated with Cells Bearing Stem Cell Markers

Introduction: It is still uncertain whether metastasis is predominantly an early or late event in tumor progression. The detection of early metastases and cells responsible for the dissemination may therefore have significant clinical implications. Methods: Lung dissemination and/or metastasis were investigated in mice carrying the polyomavirus middle-T oncogene (PyMT) during different stages of mammary tumorigenesis using the colony forming assay. Immunocytochemical or immunohistochemical staining was used to identify subpopulations of cells responsible for lung dissemination and metastasis. Histological examination was used to show primary and metastatic tumors. The tumor-initiating and metastatic capacity of cells expressing stem cell markers was assessed in syngeneic wild-type (WT) mice whose mammary fat pads were injected with these cells. Results: Metastatic mammary epithelial cells were detected in the lungs of mice carrying the PyMT oncogene (MMT mice). These cells were observed early in breast tumorigenesis when the mammary tree appeared by histological inspection to be normal (or at a premalignant stage), suggesting the possession of disseminating and metastatic capacity even before full malignant transformation. Some of the disseminated cells and lung metastases displayed surface stem cell markers. These findings suggest that stem cells from apparently precancerous primary lesions could be a source of metastasis. Indeed, injection of lung tissue cells from MMT mice into syngeneic WT mice resulted in the formation of mammary tumors. These tumors resembled their parent mammary tumors in the MMT donors as well as grafted tumors derived from mammary tumor cells. Furthermore, when we injected lung tissue cells from GFP MMT mice into the fat pads of recipient WT mice, disseminated or metastatic GFP-expressing cells were detected in the lungs, lymph nodes and blood of the recipient WT mice. We finally identified a subpopulation of mammary epithelial/tumor cells expressing CD44 and Sca1 that was largely responsible for dissemination and metastasis in MMT mice. Conclusions: The tumorigenic and metastatic potential of a subpopulation of mammary epithelial/tumor cells in MMT mice is endowed relatively early in mammary neoplasms and suggests a potential role for cancer stem cell sub-populations in metastasis

Cancer Vaccine by Fusions of Dendritic and Cancer Cells

Dendritic cells (DCs) are potent antigen-presenting cells and play a central role in the initiation and regulation of primary immune responses. Therefore, their use for the active immunotherapy against cancers has been studied with considerable interest. The fusion of DCs with whole tumor cells represents in many ways an ideal approach to deliver, process, and subsequently present a broad array of tumor-associated antigens, including those yet to be unidentified, in the context of DCs-derived costimulatory molecules. DCs/tumor fusion vaccine stimulates potent antitumor immunity in the animal tumor models. In the human studies, T cells stimulated by DC/tumor fusion cells are effective in lysis of tumor cells that are used as the fusion partner. In the clinical trials, clinical and immunological responses were observed in patients with advanced stage of malignant tumors after being vaccinated with DC/tumor fusion cells, although the antitumor effect is not as vigorous as in the animal tumor models. This review summarizes recent advances in concepts and techniques that are providing new impulses to DCs/tumor fusions-based cancer vaccination