bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inhibition of cervical cancer cell growth by IL-24 (101.22)
Authors: Lee Ki-Mo , Kang Hyung-Sik 
Published: January 2023

Abstract
HeLa cervical cancer cells stably overexpressing human papilomavirus (HPV)16 E6, HE6F cells, were established to investigate the growth inhibitory effect by interleukin-24 (IL-24). The expression of angiogenesis-associated genes was upregulated in HE6F cells compared to that in mock-transfection control cells, which led to the suppression of apoptosis and consequent the augmentation of their growth. However, when HE6F cells were treated with recombinant human IL-24 (rhIL-24), the growth was inhibited by downregulation of angiogenesis-associated gene expression and induction of apoptosis. In our previous results, overexpression of Axl receptor tyrosine kinase was induced by HPV16 E6 in cervical cancer cells. To investigate whether growth inhibition of HE6F cells induced by rhIL-24 is accomplished through the regulation of Axl expression, Axl promoter assay and western blot analysis were performed. We found that rhIL-24 inhibited the growth of HE6F cells via induction of downregulated Axl expression in both transcriptional and translational levels.
A critical role for mast cells in TLR2-mediated inhibition of tumor growth in vivo (101.24)
Authors: Oldford Sharon , Haidl Ian , Howatt Mackenzie , Leiva Carlos , Johnston Brent , Marshall Jean 
Published: January 2023

Abstract
Mast cells are abundant surrounding solid tumors where they typically promote angiogenesis and enhance tumor growth and metastasis. In the context of infection, mast cells respond to pathogens via innate immune receptors, including TLR, to produce mediators which aid host defense and cell recruitment. Some TLR agonists are effective in tumor immunotherapy but the role of mast cells in their mechanism of action is unclear. Using a melanoma model in wild-type C57BL/6 and mast cell deficient KitW-sh/W-sh mice, mast cells were shown to be crucial for TLR2-agonist (Pam3CSK4) induced tumor growth inhibition. Activation of TLR2 on mast cells reversed their established pro-tumorigenic role. The tumor inhibitory effects of Pam3CSK4 were restored in KitW-sh/W-sh mice by local reconstitution with wild-type, but not TLR2-deficient mast cells. Tumor growth inhibition occurred independent of mast cell derived TNF and tumor cytotoxicity but was associated with angiogenesis suppression and NK and T cell recruitment. The mast cell mediated, tumor inhibitory effects of Pam3CSK4 were also observed in an LLC1 lung cancer model. This study reveals a novel mechanism of action for TLR2 agonists in vivo and has important implications for the design of immunotherapeutic strategies harnessing the innate immune functions of mast cells.
Conditional expression of tissue-specific antigen regulates CD8 T cell tolerance induction (101.3)
Authors: Huang Lan , Lacuanan Aimee , Eisenlohr Laurence 
Published: January 2023

Abstract
We have developed a carefully-designed transgenic model to learn how expression of an autoantigen influences the degree and nature of tolerance. The surrogate antigen, directed to thyroid by a tissue-specific promoter, consists of a cell-surface glycoprotein (human interleukin-2 receptor α chain, Tac) to which well-defined B cell, CD8+ T cell, and CD4+ T cell epitopes have been appended in order to assess all three lymphocyte subset responses. A LoxP-flanked stop cassette was inserted between the tissue-specific promoter and the transgene open reading frame (ORF) to allow for conditional expression. To avoid positional and copy number effects in traditional transgenesis, the transgene was targeted to HPRT locus with a single-copy insertion. Here we show that embryonic but not adult expression of Tac transgene results in a profound epitope-specific CD8 T cell tolerance. However, prolonged expression of postnatal antigen is able to facilitate tolerance induction. Moreover, the ability to induce Tac-specific immune tolerance correlates with the loss of susceptibility to rejection of Tac-expressing tumor cells. These findings provide direct evidence of dynamic tolerance induction to normal or tumor antigens.
The effect of alpha2M levels on the immunogenicity of HSP-peptide complexes (101.32)
Authors: Zhou Yu , Binder Robert 
Published: January 2023

Abstract
CD91 is an endocytic receptor on Antigen Presenting Cells for the immunogenic Heat Shock Proteins (HSPs) gp96, hsp70, hsp90 and calreticulin. Binding of HSPs to CD91 initiates immune responses through cross presentation of the HSP-chaperoned peptides and elaboration of co-stimulatory signals. In vitro, various CD91 ligands compete with HSPs for receptor binding; the serum protein alpha-2-macroglobulin (a2M) is one such ligand. In light of this observation, we hypothesize that modulation of a2M levels in animals will affect the immunogenicity of HSP-vaccines. Elevated levels of a2M are achieved by initiating an acute inflammatory response and monitored by ELISA. Immune responses following HSP vaccination are measured by in vivo CTL assays. The results from these experiments will impact on-going and future clinical trials in cancer patients vaccinated with HSP-peptide complexes.
Secretory Leukocyte Protease Inhibitor (SLPI) delays development of murine squamous cell carcinoma and inhibits metastasis. W Jin, J Wen, MF Starost, G McGrady, SD Shapiro and SM Wahl, OIIB, NIDCR, NIH, and DVR, NIH, Bethesda, MD and Univ Pittsburg, Pittsburg, PA. (101.33)
Authors: Jin Wenwen , Wen Jie , Starost Matthew , McGrady George , Shapiro Steven , Wahl Sharon 
Published: January 2023

Abstract
Development of squamous cell carcinomas (SCC) represents a multistage process of transformation, invasion and metastasis dependent on genetic aberrancies and contributions of surrounding stroma. Dissemination to distant sites depends on proteolytic enzymes to enable migration and entry into vessels, underscored by a protease-protease inhibitor imbalance. Deletion of SLPI, a serine protease inhibitor expressed in most epithelia, which potently inhibits elastase, is linked to altered tumor progression. In rodents, SLPI is also generated by inflammatory cells, and has antimicrobial and anti-inflammatory activities, in addition to inhibition of proteases. To establish which of these functions are critical in regulating tumorigenesis, we chemically induced SCC in SLPI null and wildtype mice and monitored skin tumor progression, invasion and lung metastasis. In the absence of SLPI, increased inflammatory infiltrates in pre-malignant skin tissues along with more evident protease accumulation was associated with earlier papilloma development, but malignant transformation from the papilloma, once formed, to SCC was similar in null and wildtype mice. Subsequent tumor cell invasion and metastasis to the lungs was significantly enhanced in the absence of SLPI. Resetting the balance of protease-protease inhibitor through deletion of elastase (elastase null) abrogated tumorigenesis, suggesting that elastase promotes tumor progression if unopposed by its endogenous inhibitor, SLPI.
Peroxiredoxin 1 stimulates secretion of proinflammatory cytokines by interacting with Toll-Like Receptor 4 (101.34)
Authors: Riddell Jonah , Minderman Hans , Wong Xiang , Gollnick Sandra 
Published: January 2023

Abstract
Elevated Peroxiredoxin 1 (Prx1) expression is a poor prognostic factor in various cancers. Prx1 is an intracellular antioxidant and molecular chaperone protein that is non-classically secreted from transformed or stressed cells. Prx1 was found to increase the maturation state and secretion of pro-inflammatory cytokines from macrophages and dendritic cells in a Toll-Like Receptor (TLR4) dependent manner. Prx1 bound macrophages in a saturable, competitive, and TLR4 dependent manner. Prx1 immunoprecipitated and colocalized with TLR4. Extracellular Prx1 increased nuclear factor kappa B (NF-kB) translocation and DNA binding activity in a TLR4 dependent manner. In vivo, Prx1 injected intravenously in mice increased systemic interleukin 6 (IL-6) levels in a TLR4 dependent manner. Prx1 promotes innate immunity through the interaction in TLR4; however, the role of extracellular Prx1 in cancer remains undefined. Prx1 delayed tumor growth in prostate cancer models and additionally affected the numbers of CD11b+ Gr1HI F4/80+ tumor associated macrophages that have been identified as a myeloid derived suppressor cell population. This is the first time that extracellular Prx1 is demonstrated to interact with TLR4 on immune cells and that the interaction has consequential effects on macrophage populations and tumor progression.
Cytotoxic chemotherapy rescues tumor-driven aberrant CD4+ T cell differentiation and restores an activated polyfunctional helper phenotype (101.9)
Authors: Zhou Gang , Ding Zhi-Chun , Blazar Bruce , Mellor Andrew , Munn David 
Published: January 2023

Abstract
The functional development of tumor-specific CD4+ T cells critically impacts the outcome of anti-tumor immune responses. Adoptive immunotherapy involving tumor-specific CD4+ T cells has shown encouraging clinical benefits in some cancer patients. In order to mount an effective anti-tumor immunity, it is desirable to elicit activated type 1 T helper cells (Th1). In this study, we report that Th1-like effector cells that arose in tumor-bearing hosts progressively expressed Programmed Death 1 (PD-1) during tumor growth. The PD-1hi effector cells displayed a dysfunctional phenotype, characterized by heightened apoptosis and poor anti-tumor efficacy. This tumor-driven aberrant T cell response could be prevented by a single dose of the widely-used chemotherapy agent cyclophosphamide. We show that chemotherapy conditioned the host environment, creating a transient window for optimal effector differentiation for adoptively transferred CD4+ T cells. This robust effector differentiation, which was antigen-driven and mechanistically dependent on an intact host response to type I interferon, gave rise to activated polyfunctional T helper cells with potent anti-tumor activity against established B cell lymphomas. We hypothesize that prevention of tumor-induced effector cell dysfunction is a major mechanism contributing to the efficacy of combined chemo-immunotherapy.
Computational studies of B cell receptor diffusion can elucidate the mechanism of B cell synapse formation (130.1)
Authors: Raychaudhuri Subhadip , Tsourkas Philippos 
Published: January 2023

Abstract
B cell receptor (BCR) clustering in the form of an immune synapse (membrane-bound antigens) or a cap structure (soluble antigens) is a central event in adaptive immunity because such BCR clustering takes part in BCR recognition of non-self antigens. We approached the problem of B cell synapse formation using a Monte Carlo computational study of B cell receptor diffusion at a single molecule level. Recent experiments (Immunol. Rev. 221:64-76 2008), based on single molecule tracking, have elucidated that BCR molecules diffuse at a much slower rate in the regions of antigen binding. The mean-square displacement of BCR molecules, as obtained from our computational studies, shows an affinity dependent sub-diffusive behavior indicating an affinity dependent mechanism of B cell receptor clustering in immunological synapses. Parallel theoretical analysis in a simplified model system clarified how binding of receptor-ligand pairs at a curved cell-bilayer junction could lead to affinity-dependent sub-diffusive behavior. Our recent efforts in this direction are focused on exploring various possible mechanisms of biased transport of BCR molecules. Initial results indicate biased diffusion can also generate sub-diffusion, albeit in an affinity-independent manner, and such biased transport is necessary for BCR clustering in immunological synapses.
A Thr/Ser-based signal in the cytoplasmic tail regulates the functional expression of human CD1d following an HSV infection (130.21)
Authors: Liu Jianyun , Glosson Nicole , Du Wenjun , Gervay-Hague Jacquelyn , Brutkiewicz Randy 
Published: January 2023

Abstract
CD1d molecules are MHC class I-like molecules that present lipids to a unique subpopulation of T cells called natural killer T (NKT) cells. We have previously shown that the Thr322 residue in the cytoplasmic tail of human CD1d is important for its intracellular trafficking and functional expression. We proposed that the phosphorylation of T322 is a signal for CD1d lysosomal targeting and degradation. In the current study, we generated dual mutants by substituting the T322 and S323 residues with Ala (non-phosphorylatable) or Asp (mimicking phosphorylation) and expressed them in human 293 cells. We found that the surface expression level of the CD1d mutants was in this order: T322AS323A&gt;WT&gt;T322A&gt;S323A&gt;S323D&gt;T322D&gt;T322DS323D. Our results suggest that the phosphorylation of both T322 and S323 has a cumulative negative effect on the functional expression of CD1d. Interestingly, substitution of the T322 and S323 residues with Ala inhibited CD1d degradation and prevented a decrease in CD1d-mediated antigen presentation following an HSV infection. This suggests that the T322/S323 dyad may be phosphorylated and target CD1d for lysosomal degradation during a viral infection as a means of immune evasion. Thus, our findings strongly suggest that T322 and S323 form a dual residue motif that can regulate the functional expression of CD1d.
CD99 differentially modulate transcriptional regulation of classical MHC class I and CD1a molecules (130.23)
Authors: Mahiddine Karim , Bernard Ghislaine , Larbret Frederic , Mallavialle Aude , Bzioueche Hanene , Bernard Alain 
Published: January 2023

Abstract
We have previously established that CD99, a ubiquitous surface molecule expressed as two isoforms, could regulate classical MHC class I (class I) expression. Fine tuning of class I during differentiation and activation of professional APC should be crucial event which deserve to be carefully examinated. Surprisingly, we found that expression of CD1a was inversely regulated to class I expression by a mechanism involving CD99. Using the Jurkat cell line, we have demonstrated that Class I and CD1a transcriptions levels are dictated by CD99 long isoform (CD99LF). CD99LF enhances Class I transcription and therefore its expression, while down regulating CD1a. We also showed that this regulation is counteracted in the presence of CD99 short form (CD99SF). Therefore, expression of both CD99 isoforms allows expression of class I and non classical MHC CD1a molecules at plasma membrane without requiring β2M modulation. To confirm our results, we used CD14+ monocytes and their derived dendritic cells. Performing qRT-PCR, flow cytometry and CD99 silencing experiments, we have demonstrated that generation of CD1a positive dendritic cells (mDC1) depends on a mechanism involving an expression switch from CD99LF to both CD99 isoforms. We hypothesize that lack of CD99 switches leads to CD1a negative (mDC2) generation. This regulatory mechanism appears to be therefore crucial for mDC1 or mDC2 orientations, which are distinguished by their different capacities to direct Th cell differentiation.
Immune cross recognition of a conserved Flavivirus epitope (130.28)
Authors: McMurtrey Curtis , Piazza Paolo , Meeks Janet , Bardet Wilfried , Buchli Rico , Imrie Allison , Rinaldo Charles , Hildebrand William 
Published: January 2023

Abstract
We previously characterized an immunodomiant, HLA-A*0201 restricted, West Nile virus (WNV) peptide determinant. This dominant WNV peptide epitope, termed SVG9, lies within a highly conserved region of the envelope glycoprotein and demonstrates 100% homology among contemporary WNV strains. This region of the virus envelope is also highly conserved among other Flaviviruses such as Japanese encephalitis virus and Dengue virus (DV). Since immune cross reactivity has been reported within the Dengue virus serogroup, we hypothesized that T cells specific for this A*0201 restricted WNV stretch of envelope would cross-recognize different flaviviruses due to epitope conservation. As an initial test of this hypothesis we synthesized the corresponding envelope peptide for WNV (SVG9) and DV type 1 (SIG9). We utilized a competitive peptide binding assay to demonstrate that SVG9 and SIG9 have comparable and high A*0201 binding affinities. We then utilized PBMC from WNV and DV1 seropositive donors to assess T cell cross recognition of SVG9 and SIG9. T cells specific for the WNV SVG9 were cross-reactive for their DV1 Flaviviral counterpart SIG 9 and vice versa. These data demonstrate that cellular immunity is cross-reactive among different Flaviviruses. This observation has implications for vaccine development and for unraveling the immunopathology associated with infection.
Small molecule enhancers of peptide binding to MHC class II: Implications for DM function (130.40)
Authors: Call Melissa , Xing Xuechao , Cuny Gregory , Stein Ross , Wucherpfennig Kai 
Published: January 2023

Abstract
MHC II molecules present peptides derived from exogenous protein antigens. Antigens are delivered through the endosomal/lysosomal pathway to the MIIC which contains DM. Nascent MHC II molecules are directed to this same compartment through association with the invariant chain (Ii). During this process Ii is progressively cleaved leaving the placeholder peptide CLIP in the peptide binding groove of the newly translated MHC II molecule. In the MIIC, DM facilitates the exchange of CLIP peptide for high affinity peptides derived from internalized antigens before export of MHC II to the cell surface. Peptides bound to MHC II are generally very stable and can have half lives of days to weeks, while MHC II molecules that have lost peptide rapidly denature, preventing opportunistic binding of unsuitable peptides at the cell surface. These mechanisms greatly hinder peptide immunogenicity as unstructured peptide do not survive to intersect with the MIIC and there is a paucity of empty MHC II receptors on the cell surface to accept exogenously supplied peptides. Through high-throughput screening efforts we have found a number of small molecules that enhance peptide binding to MHC II. One of these small molecules is able to mimic the function of DM at the cell surface and greatly enhances peptide display in vivo. Modeling of putative small molecule interaction sites has led to the discovery of residues that are critical for DM function.
Exposure of murine macrophages to carbon nanoparticles promotes inflammation and inhibits phagocytosis (130.5)
Authors: Suro Raquel , Garza, PhD Kristine 
Published: January 2023

Abstract
Exposure to respirable ultrafine particles (2.5 μM) can adversely affect human health and have been implicated with episodes of increased respiratory diseases such as asthma and allergies; the same is predicted for nanoparticles, which can reach deeper regions of the lung. The objective of this investigation was to examine the effects of carbon nanoparticles on alveolar macrophages. Macrophages (MΦ) function as the first line of defense against invading pathogens and are likely to be amongst the first cells affected by nanoparticulates. We focused on two manufactured nanoparticles: multiwalled carbon nanotube aggregates and black-carbon. The two were tested against MΦ in a chronic contact model. We hypothesized that exposure to nanoparticles would decrease MΦ ability to effectively respond to immunological challenge. Production of interleukin (IL)-12 and nitric oxide (NO), as well as phagocytosis, and MΦ activation were examined in response to lipopolysaccharide (LPS) following a 144 hr exposure to the nanoparticles. Data demonstrated an increase in NO and IL-12 production, a decrease in phagocytosis, and a decrease in the expression levels of activation markers. The data suggests that carbon nanoparticle exposure alters MΦ responses to LPS marked by increased inflammation while potentially limiting clearance and ability to interact with effector T-cells. Thus, physiological exposure to carbon nanoparticles could potentially lead to ineffective pulmonary immunity.
Chronice leptin exposure alters dendritic cell function (130.7)
Authors: Granados Valerie , Ramirez Oscar , Garza Kristine 
Published: January 2023

Abstract
Leptin is a pleiotropic cytokine/hormone that has been shown to play a critical role in immunity, including dendritic cells (DC). In vitro experiments in mice and humans have shown that short term leptin treatment results in enhanced DC function. We hypothesized that chronic exposure, as would occur in vivo, would lead to decreased DC function. Bone marrow (BM) stem cells were thus procured from female C57Bl/6 mice and were treated with leptin during the entire DC differentiation culture period. The chronic leptin-treated BM-DC and control BM-DC (no leptin) were analyzed for phenotype, activation, and phagocytosis. The data varied extensively where leptin treatment resulted in decreased, similar, or enhanced DC function in comparison to controls as determined by expression levels of activation markers, interleukin-12 production, and phagocytosis of fluorescently-labeled E. coli fragments. To evaluate the potential role of female hormones on this outcome, the experiments were repeated with male BM-DC. Interestingly, leptin-treatment consistently decreased DC function relative to controls. The data suggests that constitutive leptin exposure may negatively regulate DC function and is additionally affected by the stage of the estrous cycle in females. The results underscore the complexity of leptin activity on immune cells that is not readily ascertained with short term exposure experiments.
Retrovirally expressed 4-1BBL dramatically increases proliferation and in vivo persistence of adoptively transferred CD19-targeted T cells, promoting complete tumor elimination. (131.16)
Authors: Condomines Maud , Plotkin Jason , Markley John , Gunset Gertrude , Sadelain Michel 
Published: January 2023

Abstract
Human T cells transduced with a chimeric antigen receptor (CAR) composed of an antibody-derived scFv fragment and the CD3ζ chain can recognize and kill tumor cells on binding to the targeted membrane antigen. The co-transduction of a CAR along with CD80 and 4-1BBL induces auto-costimulation enabling high in vivo T cell expansion and tumor rejection in a prostate tumor model. Here we investigated this concept in T cells harboring either a first generation anti-CD19 CAR (19z1) or a second generation CAR (1928z), which additionally comprises the CD28 cytoplasmic domain. We compared the proliferation and anti-tumor activity of 19z1+, 19z1-4-1BBL+, 19z1-CD80+4-1BBL+, 1928z+ and 1928z-4-1BBL+ transduced T cells in a pro B cell leukemia model (NALM-6). Seven days after IV injection into NALM-6 bearing NOD/SCID/IL2Rγnull mice, 1928z-4-1BBL+ CD8 and CD4 T cells accumulated in the bone marrow and the spleen 100 times more than 19z1+ T cells and 10 times more than 1928z+ T cells, corroborating in vitro proliferative responses to repeated antigen exposure. An increased proportion of central memory CD8 T cells was observed in all groups treated with 4-1BBL-expressing cells. Within 15 days, in vivo bioluminescence imaging showed total tumor regression in the 1928z-4-1BBL+ T cell-treated group and partial regression in the other groups. Thus, constitutive 4-1BBL expression drives high proliferation of anti-tumor CD8 T cells, promoting central memory T cell persistence and tumor eradication.