bluuebunny/crossref_metadata_2025_split huggingface dataset:
Chimeric Mesothelin Virus-like Particle Vaccine Induces Strong Anti-tumor Immunity against Pancreatic Cancer by Activating Plasmacytoid Dendritic Cells and Reducing CD4+foxp3+ ICOS- Regulatory T cells (41.28)
Authors: Zhang Sheng , Cubas Rafael , Li Min , Chen Changyi , Yao Qizhi 
Published: January 2023

Abstract
Abstract
Our previous study has shown that mesothelin (MSLN) is highly expressed in pancreatic cancer and can be used as an immunotherapeutic target. Here, we further deciphered the effective anti-tumor immune responses elicited by vaccination of virus-like particle (VLP) that highly express murine MSLN (mMSLN) on their surface. In an orthotopic pancreatic cancer mouse model, we found that mMSLN-VLP immunization showed strong anti-pancreatic cancer effects leading to significantly reduced tumor volume and longer survival compared with the VLP control. Elevated MSLN-specific IFN-γ secreting CD8+ T cells, MSLN-specific tetramer positive CD8+ T cells, and MSLN-specific cytotoxic T cells were found in mMSLN-VLP immunized groups. More importantly, progressively decreased percentage of CD4+foxp3+ regulatory T cells (Tregs) cells was found in all VLP immunized groups in both spleen and tumor sites with multiple VLP immunizations. Interestingly, this reduced CD4+foxp3+ Treg population was composed of mostly high ICOS-expressing cells. Furthermore, VLPs activated plasmacytoid dendritic cells (pDCs) and increased IL-6 production, which led to the survival of CD4+foxp3+ICOS+ Tregs. Blockage of IL-6 partially rescued the reduction of ICOS-foxp3+ Treg in splenocytes. Thus, the efficacy of a MSLN-VLP tumor vaccine may lie not only in the induction of a tumor specific CD8+ T cell response, but also in eliciting strong immune responses by activating pDCs and the reduction of CD4+foxp3+ICOS- Treg sub-populations to control MSLN over-expressing tumor progression.
Tumor-derived Autophagosomes is a Potent Vaccine in Cancer Immunotherapy (41.33)
Authors: Li Yuhuan , Pang Puiyi , Urba Walter , Fox Bernard A , Hu Hong-Ming 
Published: January 2023

Abstract
Active immunotherapy (AIT) using vaccines has been exploited to eradicate primary tumors and metastases; however, overall clinical response rate of AIT is less than 4%. This disappointing result underscores the need for novel vaccines. We have developed an autophagosome-enriched vaccine (DRibble), and evaluated its efficiency in cross-presentation of tumor-associated antigens (TAA) and its anti-tumor efficacy. We found that autophagosomes can accumulate and be released from a number of tumor cell lines after prolonged inhibition of proteasome-mediated protein degradation. By transmission electron microscopy, we confirmed the presence of numerous double-membrane autophagosomes in DRibble preparations from tumor cells. The DRibbles sequestered long-lived and short-lived proteins, defective ribosomal products, as well as heat shock proteins HSP90 and HSP94, as evidenced by western blotting. Using CFSE dilution of labeled antigen-specific TCR transgenic CD8+ T cells as a read out, we showed that DRibbles were highly efficient in cross-presenting TAA in vitro and in vivo. Vaccination with DCs loaded with gp100-DRibbles resulted in a doubling of median survival time of mice bearing 6-day s.c. B16F10 tumors (59 days for vaccinated mice vs 26 days for untreated mice). Remarkably, 83% of mice bearing 6-day s.c. 3LL tumors were cured when they received DRibble vaccines, whereas all untreated mice succumbed to disease. Based on these strong preclinical results, our Institute has initiated a clinical trial for non-small cell lung cancer using autologous tumor-derived DRibbles. This work was supported by NIH grants CA 107243 (HMH), CA 123864 (WJU), ACS grant LIB-106810 (HMH), the Providence Medical Foundation, and the Kuui Foundation.
Adoptive T Cell Therapy Targeting WT1 in Leukemia and MDS patients (41.34)
Authors: Ragnarsson Gunnar , Nguyen Hieu , Chaney Colette , Ho Bill , Greenberg Phil 
Published: January 2023

Abstract
Objectives: A clinical trial is being performed to primarily determine the safety in leukemia patients of targeting WT1, a transcription factor over-expressed in leukemia cells that promotes the malignant phenotype, by adoptive transfer of WT1-specific CD8+ clones (CTL). The secondary objectives are to assess in vivo persistence of transferred CTL, localization of transferred cells to bone marrow (BM), and potential antileukemic activity.
Methods: HLA-A0201+ patients with relapsed Acute Leukemia, Chronic Myeloid Leukemia or Myelodysplastic Syndrome after allogeneic hematopoietic cell transplant receive 5 infusions, with the last two followed by IL2, of CTL (3.3x10 8-1.0x1010 cells/m2) derived from their matched donor.
Results: Four patients have now completed and a fifth patient started therapy. No significant treatment related toxicities were observed in patients who completed therapy. WT1 was elevated in PBMC in 1 patient prior to therapy (a marker of minimal residual disease), and became undetectable after therapy. A second patient exhibited reduction in leukemic blasts after CTL infusion (11.8% to 1.8% of PBMC). The infused CTL persisted for up to 2 weeks in PBMC and were detected in the BM after CTL infusions.
Conclusion: The preliminary results suggest infusion of WT1-specific CD8+ clones is safe; and that CTL can localize to the BM and may have anti-leukemic activity.
Support: NCI CA18029 & LLS 4442-09
Histone deacetylase inhibitor, LBH589, synergizes with an immunotherapy treatment in an in vivo murine brain tumor model (41.35)
Authors: Lisiero Dominique Naomi , Soto Horacio , Fang Shanna , Ribas Antoni , Liau Linda , Prins Robert 
Published: January 2023

Abstract
Cancer immunotherapy treatments may show low response rates due to an anti-apoptotic tumor environment. We hypothesized a treatment of immunotherapy and histone deacetylase inhibitor, LBH589, could induce tumor cell expression of pro-apoptotic molecules and sensitize these cells to immune mediated cell death.
Treatment with adoptive transfer immunotherapy and LBH589 resulted in synergistically reduced s.c. tumor burden, and prolonged survival in an intracranial tumor model. In vivo studies in non-tumor bearing mice treated with this combination therapy showed a 2-fold increase in the number of adoptively transferred cells in comparison to an immunotherapy alone treatment group. Furthermore, combination treatment also showed a 2-fold increase in ex vivo interferon-γ secretion with and without stimulation of hgp100 peptide in comparison to an immunotherapy alone group. However, overall levels of histone 3 lysine acetylation in these adoptively transferred CD8+ T-cells do not change between treatment groups.
Our results suggest LBH589 enhances immunotherapy treatment by decreasing tumor burden and increasing survival in a murine melanoma brain tumor model. Furthermore, treatment with LBH589 increases CD8+ T-cell secretion of interferon-γ in the absence and presence of peptide, and this does not appear to be caused by a change in overall histone 3 lysine acetylation levels.
Early Hematopoietic Zinc Finger (EHZF/ZNF521) prevents tumor cell recognition by Natural Killer cells. (41.43)
Authors: carbone ennio , La Rocca Rosanna , Bond Heather M. , Giovanni Morrone , fulciniti mariateresa , mazzei valerio , Tadepally Laksmikanth , mesuraca maria , ferrone soldano , gulletta elio , catalano lucio , rotoli bruno , grieco michele 
Published: January 2023

Abstract
EHZF/ZNF521 is a novel zinc finger protein expressed in hematopoietic stem and progenitor cells and is downregulated during their differentiation. Its transcript is also abundant in some hematopoietic malignancies. Analysis of the changes in the antigenic profile of cells transfected with EHZF cDNA revealed upregulation of HLA class I cell surface expression. This phenotypic change was associated with increased level of HLA class I heavy chain, in absence of detectable changes in the expression of other antigen processing machinery (APM) components. Enhanced resistance of target cells to NK cell-mediated cytotoxicity was induced by enforced expression of EHZF in the cervical carcinoma cell line HeLa and in the B-lymphoblastoid cell line IM9. Preincubation of transfected cells with HLA class I antigen-specific mAb restored target cell susceptibility to NK cell-mediated lysis, indicating a specific role for HLA class I antigen upregulation in the NK resistance induced by EHZF. A potential clinical significance of these findings is further suggested by the inverse correlation between EHZF and MHC class I expression levels, and autologous NK susceptibility of freshly explanted multiple myeloma cells.
Mutant gp70 as a source of a novel CT26 tumour antigen, GSW11 (41.46)
Authors: Bailey Ian G , Reeves Emma , Elliott Tim , James Edd 
Published: January 2023

Abstract
There is accumulating evidence that CD4+ CD25+ regulatory T cells (Treg) play an important role in anti-tumour immunity by preventing effective T cell responses to tumour antigens. Tregs have also been shown to inhibit development of organ-specific autoimmune diseases suggesting they inhibit immune responses to tissue-specific self-antigens. The depletion of Tregs prior to challenge with the murine colorectal tumour, CT26, stimulates a robust, protective T cell response which is also protective to challenge with other tumours of different histological origins, such as B cell lymphomas and a renal cell carcinoma. This cross protection has not been seen with other tumour cell lines. We have identified a CT26-derived cross-protective antigen, GSW11, which was found to be encoded within the ectotropic murine leukaemia virus (emv-1) envelope protein, gp70. This protein has previously been shown to encode CT26-specific CD8 and CD4 antigens, implicating it as a 'hot-spot' for CT26 tumour antigens. Interestingly, we have identified a truncated version of gp70 which may be responsible for generation of GSW11. Expression studies have revealed increased gp70 expression in CT26 compared to other tumour cell lines, indicating the ability to cross-protect is related to the quantity of antigen (GSW11) generated.
Metastatic hepatoma cell model and its mechanism of immunotolerance (41.47)
Authors: Cao Lili , Sun Wensheng , Han Lihui , Zhang Zhiyong 
Published: January 2023

Abstract
Metastatic hepatoma cells are the most dangerous parts in hepatocarcinoma patients.We want to study the mechanism of metastatic hepatoma cells to escaping from host immune attacks. Firstly, we constructed the metastatic hepatoma cell model by using plates pre-coated with Poly-HEMA and found that they were aggregated, proliferation-resistant, apoptosis-resistant, cell cycle arrested and more invasive. These metastatic hepatoma cells could settled down and proliferated again under suitable conditions. Subsequently,we investigated the response of metastatic hepatoma cells to the typical immune surveillant molecule TNF-related apoptosis-inducing ligand (TRAIL). The data indicated that metastatic hepatoma cells not only resist to TRAIL-induced apoptosis, but also express lower membrane binding TRAIL and excrete more soluble TRAIL (sTRAIL) to exert a stealth "tumor counterattack" effect to attack immune effector cells. Deeply study found that the membrane binding death receptors DR4 and DR5 were down-regulated on metastatic BEL7402 and SMMC7721 cells and that their active level of caspase-8,-9,-3 was highly restrained. So we concluded that metastatic hepatoma cells could escape from host immune system by the death receptor pathway.
This work was supported by grants from the National Natural Science Foundation of China (No.30873025, No.30700357 and No.30772031), Corresponding author E-mail:WSW@sdu.edu.cn.
Use of DLE as treatment in murine endotoxic shock (41.54)
Authors: Robledo Avila Frank Hanz , Vazquez Leyba Said Kayum , Valderrabano Ortiz Estela , De la Fuente Granada Marisol , Perez Tapia Sonia Mayra , Estrada Garcia Iris , Estrada Parra Sergio 
Published: January 2023

Abstract
The LPS is a structural component of the external membrane of the Gram negative bacteria and is the most powerful of the inflammation inductors. High doses of LPS have as consequence a high production of inflammatory cytokines, which causes the endotoxic shock. The Dializable Leukocyte Extracts (DLE) is the dialyzable fraction with lower molecular weight to12 KDa which come from leukocytes lysates. In this work a model of endotoxic shock LPS was induced established in C57BL6 male 6 weeks of age, the dose for endotoxic shock induction was 130mg/kg mouse weight. The doses of 0.001ug and 0.0001ug mDLE showed protection against endotoxic shock death in 10% of the mice and the 0.01ug mDLE dose protected against of endotoxic shock death from 10 to 30% of the mice. Levels of TNF-alpha, IL-6, IL-12, MCP-1, IFN-gamma, IL-10 and TGF-beta were measured in serum of mice endotoxic shock induced and treated with mDLE, the groups in which LPS was administrated and then treated with 0.01ug, 0.001ug or 0.0001ug of mDLE showed smaller levels of inflammatory cytokines and more higher levels of antiinflammatory cytokines than the LPS treated control group. The splenic index was measured in the endotoxic shock induced and mDLE treated groups, the group LPS and the 0.001ug of mDLE treated showed the higher splenic index in comparison with the LPS control group. So the DLE can be use as a potential therapeutic agent as adjuvant in the treatment of sepsis.
Redirection of human T lymphocytes towards HER2 by T cell receptor gene transfer for adoptive T cell transfer (41.6)
Authors: Conrad Heinke , Meyerhuber Peter , Kast Barbara , Mueller Julia , Peschel Christian , Uckert Wolfgang , Bernhard Helga 
Published: January 2023

Abstract
The clinical goal of our studies is the adoptive transfer of primary T cells transduced with a HER2-specific T cell receptor (TCR) for patients with HER2-overexpressing breast cancer.
HLA-A2-, CD8 T cells were stimulated with allogeneic HLA-A2+ dendritic cells (DC) pulsed with the peptide HER2369-377. HER2369-377-reactive T cells were screened, cloned and further tested in functional assays.
The TCR from the HER2-reactive CTL clone KU1 was cloned into a retrovirus. Primary T lymphocytes were transduced with this construct and functionally compared with the parental CTL clone KU1.
The TCR-transduced primary T cells recognized the peptide HER2369-377 exogenously loaded onto T2 cells or endogenously expressed by tumor cells and transfectants. Similar to the parental CTL clone KU1, the transgenic T cells were not only able to recognize HER2369-377, but also the corresponding peptides from HER3 and HER4. Following TCR optimization (codon optimization, murinization), the TCR-transduced T cells displayed an enhanced tumor cell recognition.
In conclusion, the fine specificity of a HER2-reactive TCR is conserved following transduction into primary T lymphocytes. These results facilitate the design of HER2-directed immunotherapies based on TCR-transduced T cells. The observed cross-recognition especially with HER3 may be beneficial as HER2 and HER3 overexpressing tumors are particularly aggressive.
DFG
Tumor-associated antigen MUC1 contains self epitopes subject to self-tolerance and tumor-associated “foreign” epitopes that elicit effective immunity: important distinction for cancer vaccines (41.60)
Authors: Ryan Sean O. , Turner Michael S. , Revers Leigh , Gariepy Jean , Finn Olivera J. 
Published: January 2023

Abstract
Human adenocarcinomas express tumor-associated antigen (TAA) MUC1 that presents to the immune system peptide epitopes as well as glycopeptide epitopes carrying tumor specific carbohydrates. In MUC1-Tg mice responses to MUC1-peptides are suppressed while vaccination with tumor-associated glycopeptides results in effective anti-MUC1 immunity. Transgene negative mice respond equally to both antigens. Using our newly generated TCR transgenic mice with peptide and glycopeptide specific TCRs, we show for the first time that peptide specific CD4 T cells transferred to MUC1-Tg mice are suppressed through mechanisms of peripheral tolerance that are not induced against MUC1-glycopeptide specific CD4 T cells. This tolerance is due to MUC1-peptide epitope presentation in the periphery of healthy MUC1-Tg mice, previously thought to occur primarily in tumor bearing mice. MUC1 glycopeptide epitopes are tumor specific and thus treated as foreign in MUC1-Tg mice, resulting in effective activation of CD4 T cells. Furthermore, glycopeptide-specific T cells provide help to enhance peptide-specific T cell responses. We conclude that TAA contain epitopes that are subject to self tolerance and also tumor specific (foreign) epitopes not affected by self tolerance. It is important to maintain this distinction in attempts to develop effective and safe cancer vaccines. (Supported by NIH T32CA82084, RO1CA56103, CBCRA/CCS)
Real time, single-cell characterization of basophilic exocytosis through carbon-fiber microelectrode amperometry (CFMA) (42.1)
Authors: Ersin Özlem H , Ge Shencheng , Haynes Christy L 
Published: January 2023

Abstract
Histamine released by previously sensitized basophils plays a crucial role in inflammation and immediate hypersensitivity reactions. Whereas ensemble-based immunohistochemical assays characterize the average release profile of cell populations, differences among individual basophils or basophil sub-populations remain largely unexplored based on technological limitations. Previous work in our lab has used microelectrochemical techniques to measure real time quantal release from single cells isolated from separate platelet and mast cell populations. Herein we report the use of carbon-fiber microelectrodes to measure the concentration and time course of single-cell histamine secretion by primary culture basophils in response to varying physiological and electrical stimuli. Future work will utilize CFMA and the patch clamp technique to probe single-cell degranulation in a polydimethylsiloxane (PDMS) microfluidic chip model of graduated complexity.
Bioassay development of cytokines produced by Th17 cells (42.16)
Authors: Soto Hortensia , Leettola Catherine , Huang Jianyong , LeFevre Nora , Ji Shaoquan 
Published: January 2023

Abstract
The description of a new subpopulation of IL-17 producing T helper cells opened a new avenue in the understanding of immune mechanisms and immune pathologies. This recently described subpopulation has been called Th17 cells, and has a different cytokine profile from the previously described subpopulations Th1 and Th2. Th1 produce IFNγ and Th2 produce IL-4, IL-5, IL-6, and IL-13. Murine Th17 cells produce a large series of cytokines: IL-17A, IL-17F, IL-21, IL-22, IL-26, IL-6 and tumor necrosis factor (TNF)α. In humans, IL-17A, IL-17F, IL-21, IL-22 have been identified as effector cytokines that are preferentially produced by Th17 cells. In this study, we describe bioassays for cytokines produced by Th17 cells. IL-17A activity was measured by its ability to induce IL-6 in human dermal fibroblast (HDF). HDF were incubated with serial dilutions of IL-17A for 48 h, and the IL-6 was measure by ELISA. hIL-17A has ED50 of 2-4 ng/ml. IL-22 bioactivity was measure using human Colo-205 cells. IL-22 is known to induce IL-10 production in endothelial cells. Colo-205 cells were treated with IL-22 for 48 h, and IL-10 was measured by ELISA. hIL-22 shows an ED50 of 0.062-0.177 ng/ml. Mouse IL-21 was measured in a proliferation assay using CTLL-2. The ED50 for mouse IL-21 is 40 ng/ml. We have successfully expressed these cytokines and shown that they have potent biological activity. BioLegend.
A flow cytometric application for screening of new anti-inflammatory compounds (42.18)
Authors: Sepulveda Homero , Rabenstein Jacob , Apgar John , Princen Fred 
Published: January 2023

Abstract
Septic shock is a major public health problem. Organ failure during sepsis has been attributed to an extensive inflammatory response. Consequently, inflammatory reactions are important targets for drug development.
Inflammatory cytokine production is the result of the activation of signaling pathways. The Toll-Like receptor (TLR) family can recognize every known human pathogen. They trigger the host defense by activating signaling pathway such as NF-kB, MAPK, AKT and JAK/STAT. The stimulation of these pathways by pathogens will lead to an activation of transcription factors and the release of cytokines that can positively or negatively influence innate and adaptive immunity. Therefore, there is great interest in developing cell signaling inhibitors as new classes of anti-inflammatory and immuno-regulatory compounds.
We have used BD Cytometric Bead Array and BD Phosflow technologies to propose a flexible application that will facilitate the screening of compound libraries to find new anti-inflammatory drug candidates. To test this approach, we used well-characterized MAPK and PI3K/AKT inhibitors in an in vitro sepsis model. Our results demonstrated that we can simultaneously monitor the effect of a given compound on cell signaling molecules and on the inflammatory cytokines released. Moreover, we were able to specifically identify the cell population involved in the process.
In conclusion, this screening approach allows researchers to quantitatively assess and correlate the release of inflammatory cytokines with the signaling state of the cell.
An in vivo model of the human CD1 antigen presenting system (42.24)
Authors: chen xiuxu , Rajesh Deepika , Roenneburg Drew A. , Zhou Ying , Hegde Subramanya , Cheng Tan-Yun , Brenner Michael B. , Moody B. Branch , Burlingham William J. , Gumperz Jenny E. 
Published: January 2023

Abstract
CD1 molecules are a family of antigen presenting molecules that present lipids and glycolipids for recognition by specialized T cells. The CD1 system has been implicated in microbial infections, autoimmune and allergic disorders, and immunological control of tumors. However, our understanding of its role in human disease remains limited because animal models that resemble the human CD1 system are lacking. Here we report that a severely immune deficient mouse engrafted with human fetal tissues and hematopoietic stem cells develops an intact human CD1 antigen presenting system. Human CD1a, b, c, and d isoforms are highly expressed in the thymic organoid that develops in the engrafted mice, and histological analysis indicates the presence of CD1a+ APCs. Moreover, CD1+ APCs are expressed in peripheral tissues including the spleen and liver, and are capable of presenting bacterial glycolipids to human T cells specific for CD1a, b, or c. Staining with CD1d tetramers detected comparable percentages of human CD1d-restricted T cells in engrafted mice and human blood, and CD1d-restricted T cells isolated from the mice expressed a characteristic Vα24+/Vβ11+ TCR and recognized the glycolipid antigen α-GalCer. These results demonstrate the functional reconstitution of the human CD1 system in a mouse model.