bluuebunny/crossref_metadata_2025_split huggingface dataset:
Self-specific memory regulatory T-cells outrun tumor-specific effector T-cells at tumor emergence to impose tumor tolerance (66.18)
Authors: Podsypanina Katrina 
Published: January 2023

Abstract
Early responses of Tregs and effector T cells (Teffs) to their first encounter with tumor cells have been poorly characterized. We show, in both implanted and in situ-induced mouse tumor models, that the appearance of tumor cells is immediately sensed by CD44hi memory Tregs that are specific for self antigens. The rapid response of these Tregs preceded and prevented activation of naive antitumor Teffs. The relative speed of the Treg versus the Teff response within the first 2-4 days determined the outcome of the antitumor immune response: tolerance or rejection. If antitumor memory Teffs were present at the time of tumor emergence, both Tregs and Teffs were recruited and activated with memory kinetics; however, the Tregs were unable to control the Teffs, which eradicated the tumor cells. This balance between effector and regulatory responses did not depend on the number of Tregs and Teffs, but rather on their memory status. Thus, in the natural setting, dominant tolerogenic immunosurveillance by self-specific memory Tregs protects tumors, just as it protects normal tissues. More generally, our results reveal that the timing of Treg and Teff engagement, determined by their memory status, is an important mode of regulation of immune responses.
Endoplasmic reticulum stress-mediated apoptosis of EBV-transformed B cells by CD70 signaling is dependent upon generation of reactive oxygen species and activation of p38 MAPK and JNK pathway (66.23)
Authors: Park Ga Bin , Kim Yeong-Seok , Lee Hyun-kyung , Song Hyunkeun , Cho Dae-Ho , Lee Wang Jae , Hur Dae Young 
Published: January 2023

Abstract
CD70 is expressed in normal activated immune cells as well as in several types of tumors. It has been established that anti-CD70 mAb induces complement-dependent death of CD70+ tumor cells, but how anti-CD70 mAb affects the intrinsic signaling is poorly defined. In this report, we show that ligation of CD70 expressed on EBV-transformed B cells induced production of reactive oxygen species (ROS) and subsequent apoptosis. We observed an early expression of endoplasmic reticulum (ER) stress response genes that preceded the release of apoptotic molecules from mitochondria and cleavage of caspases. CD70-induced apoptosis was inhibited by ER stress inhibitor salubrinal, ROS quencher NAC, and Ca2+ chelator BAPTA. We supposed that ROS generation might be the first event because NAC blocked increases of ROS and Ca2+, but BAPTA did not block ROS. We also found that CD70 stimulation activated JNK and p38. JNK inhibitor and p38 inhibitor blocked upregulation of ER stress-related genes and cleavage of caspases. Inhibition of ROS generation blocked phosphorylation of JNK and p38 and induction of ER stress-related genes. Taken together, we concluded that cross-linking of CD70 on EBVt- B cells triggered ER stress-mediated apoptosis via ROS generation and JNK and p38 MAPK activation. Our report reveals alternate mechanisms of direct apoptosis through CD70 signaling and provides data supporting CD70 as a viable target for an Ab-based therapy against EBV-related tumors.
Effects of chronic alcohol consumption on B cells in B16BL6 melanoma-bearing mice (66.24)
Authors: Zhang Hui , Zhu Zhaohui , Meadows Gary 
Published: January 2023

Abstract
We previously found that chronic alcohol consumption inhibits CD8+ T cell immunity in B16BL6 melanoma-bearing mice and also decreases their survival. Recent reports indicate that lack of B cells, especially mature B cells, compromises CD8+ T cell anti-tumor immunity. It is unknown if alcohol consumption affects B cells in tumor-bearing hosts. Herein, we studied the effects of chronic alcohol consumption on B cell phenotypes in B16BL6 melanoma-bearing mice. Alcohol consumption did not alter the number of B cells in the bone marrow (BM), spleen or lymph nodes, but decreased B cells in the peritoneal cavity (PC) and blood. Notably, the B cell number decreased 3-4 fold in blood. The percentage of CD19+IgMhiIgDlo immature B cells slightly increased in the BM. Alcohol decreased marginal zone B cells and increased CD23-CD93+ immature B cells, and did not alter follicular B cells in the spleen. The percentage of CD19+CD5+ cells increased in the PC and CD19+CD5- cells decreased. The percentage of CD21+CD23-CD19+ B cells increased 2-fold in blood while CD19+CD23+ cells decreased. Alcohol consumption altered the gene expression of sphingosine-1-phosphate (S1P) receptor-1 (SIPR1) and S1P lyase. Collectively, these data indicate that alcohol decreases mature B cells in the blood and PC by impairing B cell circulation in melanoma-bearing mice. Altered S1P/S1PR1 signaling could contribute to impaired B cell circulation.
B cells infiltrating ovarian cancer exhibit a regulatory-like phenotype. (66.26)
Authors: Nunez-Cruz Selene , Quinn III William , Connolly Denise , Scholler Nathalie 
Published: January 2023

Abstract
IL-10, an immunosuppressive cytokine, is found in the tumor environment. While it is appreciated that Toll-Like Receptors (TLRs) in combination with signals through the B cell receptor and CD40 can modulate IL-10 production by B cells, the role that TLR stimulation plays on tumor-infiltrating lymphocytes B (TIL-B) remains unclear. To study this, we used a transgenic mouse model of serous ovarian cancer (Tg-MISIIR-TAg) and ascites of ovarian cancer patients; in vivo experiments in an IL-10 reporter mouse model are ongoing. We found that early tumors contained TIL-B phenotypically similar to B220hi CD21/35 med IgMmed follicular B cells, as demonstrated by flow cytometry. As the tumor progressed, phenotype evolved from fresh isolated TIL-B with up-regulation of CD1d and CD5, and overexpression of IL-10 compared to splenic B cells. In addition, freshly harvested TIL-B from Tg-MISIIR-TAg tumors and frozen B cells from ascites of ovarian cancer patients expressed high levels of TLR4, TLR2 and TLR9. Finally, TIL-B cultured in presence of TLR agonists increased further IL-10 production compared with fresh harvested TIL-B or splenic B cells cultured in the same conditions. Taken together, our findings indicate a direct link between the increased TIL-B production of IL-10 and stimulation through TLRs. We propose that chronic exposure of B cells to the tumor microenvironment may enhance their regulatory-like phenotype and increase their receptiveness to TLR-driven IL-10 production.
Defining the molecular mechanisms that control the development of tumor dendritic cells. (66.32)
Authors: Tang Michael , Diao Jun , Cattral Mark 
Published: January 2023

Abstract
Cancer-associated inflammation contributes to tumor progression and metastasis. Defective dendritic cell (DC) function causes impaired adaptive immunity to antigens expressed by tumors. We recently found that the intra-tumor inflammatory milieu recruits and skews development of DC precursors (pre-cDC) towards a novel Gr-1+ subpopulation, which has tolerogenic properties. This transformation reduced the proliferation and expansion of antigen-specific cytotoxic T cells in tumors. We sought to identify cytokines that regulate this differentiation. Isolated pre-cDC from mice spleen was incubated with tumor-conditioned medium (TCM) derived from Lewis lung carcinoma cell line. Supernatants from cultures were collected to analyze cytokine levels. Expression of Gr-1+ on DC was monitored by flow cytometry. We found that TCM induced pre-cDC to differentiate into Gr-1+ cDC. Neutralizing anti-cytokine Ab studies revealed that IL-6 play a role in promoting Gr-1+ cDC differentiation. Pre-cDC from IL-6-/- mice showed a reduced capacity to develop into Gr-1+ cDC. TCM contained no IL-6, but it induced IL-6 secretion by pre-cDC. These findings suggested that the release of autocrine IL-6 by pre-cDC created a positive feedback loop with tumor-derived factors in TCM to promote Gr-1cDC development. Elucidation of the mechanisms by which tumor-derived factors communicate with pre-cDC will advance our understanding of the mechanisms involved in the development of impaired immune response to cancer.
Tumor-derived G-CSF promotes granulocytic MDSC development in vivo (66.34)
Authors: Waight Jeremy , Abrams Scott 
Published: January 2023

Abstract
Myeloid-derived suppressor cells (MDSC) comprise a heterogeneous population of myeloid cells with the capacity to suppress tumor immunity. Consequently, these cells represent a significant impediment to effective cancer immunotherapy. While the mechanisms by which these cells mediate immunosuppression is well-established, details on how they develop remain poorly understood. Broadly speaking, it is known that tumor-derived factors play significant roles in diverse aspects of MDSC biology. Given that MDSC accumulation is a result of altered myelopoiesis and that a major subset is granulocytic, we tested the hypothesis that tumor-derived granulocyte-colony stimulating factor (G-CSF) promotes MDSC development. Using both implantable and autochthonous mouse mammary tumor models, we observed abundant amounts of G-CSF in vivo, which correlated with a massive accumulation of granulocytic MDSC. To determine a causal role of G-CSF in MDSC generation, we established both gain- and loss-of-function approaches. First, administration of recombinant G-CSF alone elicited immunosuppressive granulocytic MDSC. Secondly, over-expression of G-CSF in G-CSF-negative tumors led to granulocytic MDSC accumulation. Lastly, inhibiting G-CSF culminated in a significant reduction of granulocytic MDSC. Collectively, our studies demonstrate the importance of tumor-derived G-CSF in MDSC development, thus providing new insights into the identity of putative targets for therapeutic applications.
HMGB1: a regulator of myeloid-derived suppressor cell potency? (66.37)
Authors: Parker Katherine , Ostrand-Rosenberg Suzanne 
Published: January 2023

Abstract
Myeloid-derived suppressor cells (MDSC) are a heterogeneous population of cells that accumulate in individuals with cancer and inflammation and play a pivotal role in tumor immunity by suppressing T-cell activation and secreting proinflammatory molecules. The suppressive capacity of MDSC is mediated by immune suppressive factors such as arginase and reactive oxygen species (ROS). Nuclear protein, High Mobility Group Box1 (HMGB1), is present in nearly all cells and is released from myeloid cells as a danger response to sepsis, infection, or arthritis. Its release promotes inflammatory responses. HMGB1 signals through a multitude of receptors including TLR4, which is expressed by MDSC. In contrast to other inflammatory mediators which increase MDSC potency, HMGB1 reduced the suppressive capacity of TLR4(-/-) and wildtype MDSC, and reduced ROS levels in TLR4(-/-) MDSC. These findings suggest that HMGB1 may diminish MDSC function and may lead to new immunotherapeutic uses of HMGB1.
Glutathione S-transferases as regulators of tumor-induced myeloid-derived suppressor cell survival (66.38)
Authors: Fitzgerald Phillip , Beury Daniel , Ostrand-Rosenberg Suzanne 
Published: January 2023

Abstract
Tumor-induced myeloid-derived suppressor cells (MDSC) are a major barrier to tumor immunotherapy because they inhibit T-cell anti-tumor immunity through various mechanisms, including cystine sequestration and production of reactive oxygen species (ROS). MDSC accumulation, suppressive potency, and survival are driven by inflammation, which also increases MDSC production of ROS. Surprisingly, ROS do not adversely affect MDSC, suggesting that MDSC neutralize endogenous ROS. Because MDSC survival is likely to be controlled by the mechanisms that protect them against endogenous ROS, we are identifying molecules that regulate ROS levels with the goal of identifying potential targets for inducing MDSC apoptosis. Glutathione (GSH) is the major antioxidant that detoxifies ROS in conjunction with various isoforms of GSH S-transferase (GST) that catalyze the detoxification process. Because of their role in detoxifying intracellular ROS, we are analyzing intracellular levels of GSH and multiple GST isoenzymes in conventional and inflammatory MDSC to understand how inflammation protects MDSC and thus promotes tumorigenesis. GST isoforms that facilitate MDSC survival will be novel drug targets for reducing tumor-induced immune suppression and facilitating tumor immunotherapy.
Key role played by a butyrophilin family gene product in human gd T cell activation (66.39)
Authors: Bonneville Marc , Harly Christelle , Guillaume Yves , Olive Daniel , Scotet Emmanuel 
Published: January 2023

Abstract
The major peripheral Vg9Vd2 T cell subset in humans is activated by small phosphorylated metabolites of the isoprenoid synthesis pathway (referred to as phosphoantigens (P-Ag)), which are overexpressed in tumor and infected cells. The molecular partners and the mechanisms involved in P-Ag-mediated activation of Vg9Vd2 T cells remain elusive. In line with the recently described implication of murine Skint-1, a butyrophilin (BTN) family-related molecule, in selection of murine gd T cells, we show that several mAbs against a human BTN-related product with yet unknown function, which is ubiquitously expressed at the surface of hemopoietic cells sensitize a broad array of target cells to specific Vg9Vd2 T cell recognition (cytolysis, cytokines release, proliferation). Although this process is Vg9Vd2 TCR-dependent and involves gamma/delta chain residues previously shown to be critical for P-Ag-induced activation, we failed to detect any significant modulation of MVA pathway genes expression, nor any increase of endogenous P-Ag (IPP/ApppI) accumulation within mAb-treated target cells. We also identified a BTN-specific mAb that specifically inhibited Vg9Vd2 T cell activation triggered by endogenous or exogenous P-Ag.Moreover BNT knockdown abrogated Vg9Vd2 responses to PAg. Taken together, our results support a unique and critical contribution of BTN-related products in the regulation of TCR-mediated activation of human Vg9Vd2 T cells.
Downstream targets of PKCβII in dendritic cell differentiation (66.4)
Authors: Spangler Haley , Carlson Louise , Lee Kelvin 
Published: January 2023

Abstract
Dendritic cells (DC) are antigen presenting cells, inducing both innate and adaptive immune responses. In a tumor setting their differentiation from progenitor cells is inhibited by tumor derived factors, resulting in an accumulation of immature DCs. When myeloid-derived DC differentiation is inhibited, these immature DCs act as myeloid derived suppressor cells (MDSCs) which support tumor growth and metastasis, as well as reduce efficacy of many therapeutic agents in cancer. Our lab has shown in humans that loss of PKCβII (a member of the PKC family of signal transduction molecules) expression blocks DC differentiation and that tumors may mediate this downregulation. It is also known that interferon regulatory factor 8 (IRF8) plays an important role myeloid cell differentiation from progenitor cells, and it is downregulated in tumor environments, inhibiting DC differentiation. In human and murine models, we determined that inhibition of PKCβII with CGP 53353 prevented differentiation of lineage negative progenitor cells to DCs as evaluated by DC phenotypic markers and allogeneic T-cell induction. We also found that PKCβII inhibition lead to a loss in IRF8 expression. Therefore we have demonstrated a role for PKCβII in DC differentiation in mice, as well as identified a line between IRF8 and PKCβII signaling during differentiation.
Differential T cell suppression through regulatory T cells (66.43)
Authors: James Edd , Bailey Ian , Reeves Emma , Elliott Tim 
Published: January 2023

Abstract
Depletion of regulatory T cells in the CT26 murine tumour model stimulates a robust protective T cell response which is also protective to challenge with other tumours of different histological origins. We have characterised a cross-protective antigen, GSW11 (GGPESFYCASW) presented by H-2Dd. This antigen was found to be encoded within the env (gp90) gene of an endogenous retrovirus emv-1 (MuLV), previously shown to encode other CT26 antigens. Further characterisation of GSW11-specific T cell responses has shown them to be suppressed by Tregs and are absent in CT26 challenged mice. In comparison, AH1-specific T cells (AH1 is a previously characterised CT26 antigen) are not suppressed. Here we show that the GSW11-specific T cell responses are present in CT26 challenged Treg replete mice for a limited period in the tumour of challenged mice. Characterisation of the AH1 and GSW11-specific T cells infiltrating the CT26 tumour reveal differences in expression of several molecules associated with cell survival and activation. These expression profiles provide an intriguing explanation for the differential suppression of tumour-specific T cells in vivo.
Combination therapy with dendritic cell based vaccination and myeloid derived suppressor cell depletion augments immunity in a murine pancreatic carcinoma model (66.8)
Authors: Pilon-Thomas Shari , Hall MacLean , Vohra Nasreen , Sarnaik Amod , Ghansah Tomar 
Published: January 2023

Abstract
Pancreatic cancer is an aggressive disease with poor prognosis. Immunotherapy may be less effective in treating pancreatic tumors due to suppression by myeloid derived suppressor cells (MDSC). In this study, we sought to determine the effect of combining MDSC depletion with dendritic cell (DC) vaccination in a murine model of pancreatic cancer. In mice, MDSC are characterized by surface expression of CD11b and Gr-1. After injection of Panc02 tumor cells, a higher percentage (29.2%) of MDSC were present in spleens of tumor-bearing mice as compared to naïve mice (6.38%, p&lt;0.05). MDSC isolated from tumor-bearing mice significantly suppressed proliferation of antigen stimulated T cells. It has been reported that Gemcitabine (Gem), a chemotherapeutic drug, can selectively target MDSC. Flow cytometry results showed a decrease in the percentage of MDSC in splenocytes from Gem-treated tumor-bearing (6.57%) compared to untreated mice (24.3%, p&lt;0.01). To study the effects of DC vaccination combined with MDSC depletion on tumor rejection, mice received PANC02 tumor cells and were treated with 3 injections of DC at 3-4 day intervals. After the final vaccination, mice received Gem. Survival was measured in 50% of mice receiving both DC vaccination and Gem (p&lt;0.05 as compared to each treatment alone). Results from this study suggest that the depletion of MDSC enhances DC induced immunity in a murine model and raises the potential for this strategy in patients with pancreatic cancer.
A novel mouse model for arenavirus hemorrhagic fever (67.20)
Authors: Schnell Fred , Mourich Dan , Iversen Patrick 
Published: January 2023

Abstract
The viral family Arenaviridae includes a number of viruses that can cause hemorrhagic fever. Arenavirus infection often involves multiple organs and can lead to capillary instability, impaired hemostasis, and death. There is a lack of treatment options available to those suffering from arenaviral hemorrhagic fever and a well established mouse model of arenaviral hemorrhagic fever would benefit preclinical testing for arenavirus antivirals or therapeutics. We have identified the FVB mouse strain, which succumbs to a hemorrhagic fever like illness when infected with lymphocytic choriomeningitis virus (LCMV). FVB mice infected with LCMV demonstrate high mortality associated with thrombocytopenia, hepatocellular and splenic necrosis, and cutaneous hemorrhage whereas C57BL/6 mice survive. Investigation of possible inflammatory mediators revealed increased IFN-g and IL-6, along with increased chemokine production, at early times after LCMV infection as compared to C57BL/6 mice. Removal of CD4+ or CD8+ cells from FVB mice at time of infection prevented mortality in all treated animals and treatment with FK506 early during infection delayed disease onset. This report offers a novel animal model for arenavirus research and pre-clinical therapeutic testing.
TLR7-mediated Type I and Type III interferon production and TLR7 movement within primary human plasmacytoid dendritic cells is stimulated by Influenza virus (67.22)
Authors: Natalia Mahwish , Singh Sukhwinder , Cui Chongwei , Fitzgeral-Bocarsly Patricia 
Published: January 2023

Abstract
Human plasmacytoid dendritic cells (pDC) recognize single stranded RNA and double stranded DNA viruses through endosomal TLR7 and -9, respectively, resulting in production of type I and III interferons (IFN). pDC produce both IFN-α and IFN-λ upon Influenza (Flu) virus stimulation; this induction of IFN is dependent on signaling through TLR7 since the TLR7 inhibitor, IRS661, inhibited Flu-induced IFN production in pDC, but not HSV-induced IFN, which signals through TLR9. Cathepsins (Cat), cysteine endolysosomal proteases, are essential for antigen processing in flu-stimulated murine DCs. We found that the broad Cat inhibitor, Z-FM-FMK, inhibited flu and HIV-induced IFN-α production by pDC, both which require processing to make their RNA accessible to TLR7, but had no effect on the small molecule TLR7 ligand Imiquimod-induced IFN production. Flu is known to enter cells via the endocytic pathway, with viral membrane fusion with the endolysosomal membrane required for the release of its viral RNA into the cytoplasm and its subsequent replication. Using ImageStream imaging flow cytometry, we observed that TLR7 is constitutively present in the EEA1 (early)- and LAMP1 (late)-positive endosomes in pDC, and, upon stimulation with flu, TLR7 co-localization with LAMP1-positive endosomes increases. Taken together, these results indicate that recognition of Flu in pDC requires virus endocytosis, Cat processing, and results in TLR7 movement from early to late endosomes and IFN production.
Contribution of 2009 pandemic swine-origin influenza virus gene segments to virulence and immunity (67.23)
Authors: Stambas John , Evans Justin , Middleton Deborah , Lowther Sue , Robinson Rachel , Haining Jessica , Payne Jean , Marsh Glenn , Laurie Karen , Bean Andrew , Stewart Cameron , Gilbertson Brad 
Published: January 2023

Abstract
Influenza A viruses cause annual epidemics and occasional global pandemics as seen in 1918, 1957, 1968 and most recently in 2009. On the 11th of June 2009 the first global pandemic of the 21st century was declared as a result of a triple reassortant virus containing gene segments from circulating swine, avian and human influenza viruses. Reverse genetics technology was used to study swine-origin influenza virus (S-OIV) virulence through the generation of reassortant influenza viruses expressing gene segments from the 2009 pandemic strain. Our results show that S-OIV gene segments are capable of altering virulence in both X31 and PR8 reassortant influenza viruses. In particular one specific X31-(S-OIV) reassortant virus showed a significant increase in virulence in mice with substantial weight loss, high virus titers and elevated levels of inflammatory mediators in the lung following infection. Moreover these findings suggest that the current H1N1 pandemic S-OIV has the potential to influence the virulence of other circulating influenza viruses in the future.