bluuebunny/crossref_metadata_2025_split huggingface dataset:
Transient Receptor Potential Ankyrin 1 Mediates the Afferent Arm of the Inflammatory Reflex
Authors: Silverman Harold A. , Addorisio Meghan , Tsaava Tea , Stiegler Andrew , Kressel Adam M. , Chin Christopher A. , Gunasekaran Manojkumar , Pavlov Valentin A. , Chavan Sangeeta S. , Tracey Kevin J. 
Published: January 2023

Abstract
The vagus nerve plays an important role in maintaining an organism’s immune homeostasis through the inflammatory reflex. Inflammatory molecules including LPS, TNF and IL-1β can mediate electrophysiological changes in vagus nerve signaling. Reasoning that these signals are mediated though specific neuronal fibers that can be identified by molecular markers, we administered endotoxin to mice that received optovin, a molecule that interacts with TRPA1 and is light sensitive. Selective stimulation of vagus nerve TRPA1+ fibers significantly reduce serum TNF levels (sham: 920.9 ± 87.9 pg/ml vs. stimulated: 456.8 ± 69.4 pg/ml). This reduction is ablated by proximal vagotomy, indicating that the signals are afferent in nature. Prior work suggests that the afferent vagus nerve is required for IL-1β induced febrile responses and sickness behavior. Here we administered IL-1β to TRPA1 KO mice and observed that body temperature was maintained as compared to wildtype (peak temperature change; wildtype: −2.35 ± 0.15 °C vs. TRPA1 KO:0.18 ± 0.40 °C). When recording electrical activity from the VN, IL-1β induces a significant increase in VN activity in WT mice. However, no significant increase is observed in TRPA1 KOs. Cecal ligation and puncture in TRPA1 KOs caused significantly higher disease severity scores, percent weight loss, and mortality. These results identify TRPA1 as both a marker for fiber specific inflammatory signaling as well as a necessary component for regulating inflammatory homeostasis.
Deficiency in Soluble FasL Terminates Ocular Immune Privilege to Promote Elimination of Intraocular Tumors
Authors: McCullough Peter , Kissinger Emily , Rothstein Ann Marshak , McKenna Kyle C. 
Published: January 2023

Abstract
The eye is a site of immune privilege exemplified by the observation that immunogenic tumor cells, for example P815 mastocytomas, that are rejected when transplanted in the skin of Balb/C J mice, grow progressively forming intraocular tumors when placed in the anterior chamber (a.c.) of the eye. The mechanisms that promote and maintain ocular immune privilege are not completely understood. However, CD95/FasL has been shown to contribute to ocular immune privilege (Griffith TS et al. 1995. Science 270:1189) and is expressed as a membrane associated molecule that can be cleaved to generate a soluble form. To begin to evaluate whether membrane or soluble FasL was required for ocular immune privilege, P815 tumor growth was monitored in mice unable to generate soluble FasL (DCS mice) due to a point mutation introduced in the FasL cleavage site. Twenty-four days after tumor challenge in the a.c. of the eye, tumor burden, measured by weight of challenged eyes, was reduced 5-fold in DCS mice in comparison to wild-type mice (DCS: 99+/−34 mg vs. Balb C/J: 20+/−15mg) and this difference was statistically significant (p&lt;0.0001) and reproducible. The weight of tumors in DCS mice was equivalent to control non tumor challenged eyes suggesting complete tumor elimination. These data suggest that soluble FasL is necessary to maintain ocular immune privilege and promote intraocular tumor growth.
Anti-tumor immunity generated as an artifact of tumor implantation determines the response to immunotherapy in murine models
Authors: Gough Michael J. , Zebertavage Lauren , Bambina Shelly , Kramer Gwen , Friedman David J. , Troesch Victoria , Blair Tiffany , Baird Jason R. , Alice Alejandro , Crittenden Marka R. 
Published: January 2023

Abstract
Cancer cell lines grown in vitro and implanted into mice are a centerpiece of preclinical modeling. However, tumor implantation is an in vivo vaccination event that can impact tumor growth. Checkpoint inhibitors targeting PD1 or CTLA4 interactions are effective at unleashing suppressed pre-existing immunity in murine models, but do not generate new immune responses.
We hypothesized that tumor control by checkpoint inhibitor immunotherapies was dependent on pre-existing immunity generated at tumor implantation.
Using cancer cells engineered to express model antigens, spontaneous tumor models with defined trackable antigens, or unmodified cancer cells, we demonstrate that tumor implantation results in initial T cell mediated immunity. As the tumors progress, these cells become undetectable in the periphery and accumulate in the tumor, but do not prevent tumor progression. While tumors respond to checkpoint inhibitors administered closely following implantation, delayed administration results in a loss of efficacy. This efficacy can be recovered by the addition of radiation therapy to checkpoint inhibitors, permitting cure of established murine tumors that are not controlled by either therapy alone. However, blocking the immune response at tumor implantation using a range of approaches results in a complete loss of efficacy of tumor control by all therapies based around checkpoint inhibitors. We demonstrate an approach to ‘silently’ establish tumors in mice to test therapies that can initiate de novo immunity to tumors.
These data have significant implications for current clinical attempts to use checkpoint inhibitors, which may not be a solution for patients without pre-existing immunity to their tumor.
Differential roles of tumoral and systemic IL-1α in the development of hepatocellular carcinoma
Authors: Liu Haiyan 
Published: January 2023

Abstract
Interleukin-1α (IL-1α) is a pro-inflammatory cytokine that has been shown to be up-regulated in many tumors. However, the role of IL-1α during tumor development is still not clear. IL-1α could be released by necrotic tumor cells passively to the tumor microenvironment or by other cells actively during inflammation. In the current study, we investigated the role of secreted IL-1α released in the tumor microenvironment or systemically in the tumor development using murine hepatocellular carcinoma (HCC) models. We constructed murine HCC hepa1-6 cells stably expressing secreted IL-1α and overexpression of secreted IL-1α had no significant effect on tumor cell proliferation and apoptosis in vitro. Tumor cells expressing secreted IL-1α were orthotopically implanted in the liver. Tumoral IL-1α significantly promoted HCC tumor development. Further studies showed that tumoral IL-1α inhibited T and NK cell activation, and attenuated the cytotoxic T lymphocyte (CTL) cytotoxic activity against tumor cells. Moreover, MDSCs were increased by tumoral IL-1α, and depletion of MDSCs could diminish the effect of the released IL-1α on tumor growth. On the contrary, systemic administration of IL-1α significantly inhibited the tumor development in the same murine HCC models. Systemic administration of IL-1α promoted T cell activation and decreased MDSCs in the tumor microenvironment. Further in vitro experiments showed that recombinant IL-1α could promote T cell activation and enhance CTL cytotoxicity. In conclusion, our studies demonstrated the differential functions of tumoral and systemic IL-1α in HCC development. Thus, our finding provides new insights of IL-1α functions in anti-tumor immunity with implications for tumor immunotherapy.
Inflammation induces GILT expression in human melanoma
Authors: Meador Lydia , Menon Hari , Cui Haiyan , Roe Denise J. , DiCaudo David J. , Hastings Karen Taraszka 
Published: January 2023

Abstract
T cell-mediated immunity can produce durable anti-melanoma responses resulting in improved survival of metastatic melanoma patients. Gamma-interferon-inducible lysosomal thiol reductase (GILT) is critical for MHC class II-restricted presentation of multiple melanoma antigens to CD4+ T cells and facilitates cross-presentation on MHC class I for activation of CD8+ T cells. Our prior study found that GILT expression is increased in melanocytes of malignant melanoma specimens compared with benign nevi. To determine whether GILT expression is associated with inflammation, expression in halo nevi specimens was compared to nevi without lymphocytic infiltrate by immunohistochemistry. A halo nevus is a benign nevus with a lymphocytic infiltrate which leads to regression of the nevus. GILT, but not MHC class II, expression was increased in melanocytes of halo nevi compared to nevi without lymphocytic infiltrate. Analysis of a publicly available gene expression profiling cohort of 457 cutaneous melanoma specimens revealed that GILT expression was associated with IFN-γ, TNF-α, and IL-1β expression in human melanoma. In vitro exposure of human melanoma cell lines to IFN-γ or inflammatory cytokines, such as TNF-α, induced GILT expression in melanoma cell lines, which lacked GILT expression at baseline. Vemurafenib, a BRAF inhibitor used in the treatment of metastatic melanoma, enhanced IFN-γ-induced GILT and MHC class II expression in a melanoma cell line. Together these data demonstrate that inflammation, alone or in combination with a current therapeutic agent, induces high levels of GILT expression in human melanoma.
Upregulating IL-15 in the tumor microenvironment promotes anti-tumor responses
Authors: Carrero Rosa Maria Santana , Beceren-Braun Figen , Rivas Sarai C. , Anthony Scott M. , Schluns Kimberly S. 
Published: January 2023

Abstract
Previous studies have shown that IL-15 expression within tumors correlates with increased tumor infiltrating T cells, decreased metastasis, and increased patient survival; however, the regulation of IL-15 within the tumor microenvironment (TME) is unclear. Examining IL-15 expression is complicated by difficulties in detecting protein and its unique mechanisms of action involving transpresentation and production of soluble IL-15/IL-15Rα complexes (sIL-15c), which are upregulated by inflammatory signals. Since we have recently shown agonists of the Stimulator of Interferon Genes (STING) pathway are potent inducers of sIL-15c in vivo, we set out to determine if sIL-15c are produced in the TME and are regulated by STING signaling. We find, in analyses of mice implanted with various tumor cell lines, sIL-15c are present at high levels in the interstitial fluid of early tumors and decrease with tumor growth. Depending on tumor type, both the tumor and the stroma are sources of sIL-15c. In analyses of IL-15 reporter mice, IL-15-expressing cells are abundant in the TME with the most predominant cells being CD11b+Ly6Chi. As cell surface IL-15 is negligible, we propose that sIL-15c are the dominant form of IL-15 produced in the TME. Despite the abundance of these IL-15 expressing cells, the relative levels of sIL-15c are low in advanced tumors but can be upregulated by local STING activation. While treatment of tumors with STING agonists leads to tumor regression, optimal STING-mediated immunity and regression of distant secondary tumors required IL-15 expression. These findings reveal the ability of IL-15 expressed within the TME to be upregulated by inflammatory signals and contribute to enhanced anti-tumor responses.
Isolation and analysis of plasma-derived exosomes in patients with glioblastoma
Authors: Garcia Luz Milbeth Cumba , Peterson Timothy E. , Cepeda Mario A. , Leong Hon S. , Johnson Aaron J. , Parney Ian F. 
Published: January 2023

Abstract
Gliomas including glioblastoma (GBM) are the most common malignant brain tumors. Glioma extracellular vesicles (EVs), especially exosomes in plasma have biological effects such as mediating immunosuppression and contain signature tumor-specific cargo, therefore could serve as liquid biopsies and as a non-invasive biomarker. However, isolation of glioma plasma exosomes has not been optimized. The purpose of this study is to develop an optimized method for plasma-derived exosomes isolation and study the immunosuppressive capacity of these particles. Plasma exosomes from glioma patients and normal donors were isolated by brief centrifugation to remove cells/debris followed by one or two-step density gradient ultracentrifugation (DGU). EV size and concentration were determined by NanoSight analysis. Nanoscale Flow Cytometry analysis quantified and characterized the resulting exosome and microvesicle populations isolated by DGU. Protein cargo was screened by Western blot, protein array, and ELISA. One-step DGU efficiently isolated exosomes for NanoSight analysis. Isocitrate dehydrogenase (IDH) WT glioma patients’ plasma exosomes were smaller but higher concentration than normal donors. A second DGU efficiently concentrated exosomes for subsequent cargo analysis. Nanoscale Flow cytometry analysis confirmed that DGU allows isolation and purification of exosomes, not microvesicles. Exosome-specific markers and the immunosuppressive molecule programmed death-ligand 1 (PD-L1), were present in both glioma patient and normal donor exosomes. Screening cytokine and checkpoint molecule arrays suggested reduced pro-inflammatory molecules are found in GBM patients’ plasma exosomes compared to normal donors.
Brain-Thymus communication as a novel immunosuppressive mechanism in the GL261 model of Glioblastoma
Authors: Ayasoufi Katayoun , Khadka Roman H. , Jin Fang , Malo Courtney Sarah , Desai Nidhi , Johnson Aaron J. 
Published: January 2023

Abstract
Glioblastoma multiforme (GBM) is incurable and among the most lethal of cancers. Immunotherapy for GBM is hampered by the fact that GBM patients are severely immunosuppressed with dangerously low T cell counts. Importantly, immunotherapy for GBM will be ineffective without defining the mechanism of immunosuppression. Given that GBM does not metastasize, we investigated the possibility of neuro-immune interactions using the GL261 glioma model in C57BL/6 mice. C57BL/6 mice harboring GL261 gliomas have abnormal thymuses which are acutely and significantly involuted compared to healthy control mice. Glioma bearing mice also have significant thymic atrophy which increases with tumor burden. Further structural analysis of the thymus in glioma bearing mice revealed disrupted thymic epithelial cells and reduced EPCAM+ cell expression of MHC II. Thymic subsets in tumor bearing mice were also developmentally skewed with increased generation of single positive T cells and a block at double negative 2 (DN2) to DN3 transition. Peripherally, MHCII expression was also significantly decreased in blood derived cells in glioma bearing mice. This correlated with an overall reduction in total CD4 T cell numbers. The results of this study demonstrate the GL261 model is recapitulating the immune suppression observed in GBM patients. These results also support the presence of a brain-thymus interaction that could negatively impact the development of immunotherapy strategies to treat GBM.
Therapeutically targeting B7-H3 via chimeric antigen receptors and bispecific killer cell engagers in non-small cell lung cancer
Authors: Zhao Qi , Liu Jie , Yang Shuo 
Published: January 2023

Abstract
Non-small-cell lung cancer (NSCLC) is the most common type of lung cancer. The B7 family antigens, such as PD-1 and its receptor B7-H1 (PD-L1), are considered therapeutic targets in NSCLC. However, little is known about the significance of other B7 family members. In this study, we determine the expression level of B7-H3 protein as a new B7 family protein in cell lines and tumor tissues from NSCLC patients by immunohistochemistry and quantitative RT-PCR. By screening in a phage displaying human antibody library, we have identified fully human antibodies specific for B7-H3 antigen. To explore B7-H3 as a potential target in NSCLC, two forms of antibody therapeutics, chimeric antigen receptor (CAR) T cells and bispecific killer cell engager (BiKE) based on one anti-B7-H3 antibody have been developed. As results, CAR T cells targeting B7-H3 demonstrated the cytotoxicity against NSCLC cells in vitro and in vivo. Meanwhile, BiKE treatment was demonstrated to significantly inhibit cell growth by inducing natural killer cells. The cytotoxicity of two agents will be further investigated in the PDX mouse models. This study suggests B7-H3 as a promising therapeutics target in NSCLC.
Antibodies targeting the intracellular liver stage malaria parasite after infection can be a potent means of reducing parasite liver burden
Authors: Sack Brandon K. , Behet Marije , Mikolajczak Sebastian , Cardamone Hayley , Nguyen Thao , Flannery Erika , Vaughan Ashley M. , Oliver Brian , Vigdorovich Vladimir , Carbonetti Sara , Sather Noah , Scholzen Anja , Sauerwein Robert , Kappe Stefan H.I 
Published: January 2023

Abstract
Malaria is one of the oldest and deadliest diseases known to humans, and in 2017 an estimated 216 million people were infected with 445,000 succumbing to disease. Antibodies which block the skin-to-liver stages of malaria infection continue to be pursued due to their potential to stop infection prior to the progression to the disease and transmission-causing blood stages. Phase III clinical trials with a vaccine targeting the major sporozoite surface protein (circumsporozoite protein) have provided suboptimal efficacy in the field which must be improved before large scale use for malaria prevention and eradication. New antibody targets will likely be needed in order to provide complete, sterilizing protection. Thus far, the search has largely been limited to targeting surface and secreted proteins of the sporozoite, merozoite or gametocyte stages.
Here, we present data demonstrating that antibodies which instead target the intracellular liver stage parasite after hepatocyte infection can be a potent means of limiting parasite liver infection in vivo. This was done in a rodent malaria model by targeting two different proteins found on the parasitophorous vacuole membrane that forms the border between parasite and host cytoplasm—indicating antibodies are entering the hepatocyte to mediate their effect. This phenomenon was also demonstrated using the most common human malaria species Plasmodium falciparum in humanized liver chimeric mice where human antibodies targeting the parasite periphery were able to potently reduce liver burden and parasite liver growth between days 5–6. These data present a new class of antibody targets for malaria and strongly argue for the inclusion of intracellular antigens in novel vaccine formulations.
Chimeric antigen receptors against HIV: Bispecific CD4-based designs for enhanced breadth/potency and minimal immunogenicity
Authors: Hajduczki Agnes , Danielson David T. , Scanlan Aaron W. , Berger Edward A. 
Published: January 2023

Abstract
Chimeric antigen receptor (CAR) technology has potential to achieve durable (life-long?) control of HIV in the absence of antiretroviral drugs, i.e. a “functional cure”. Thus in targeting the HIV-1 Env glycoprotein expressed on the surface of virus-producing cells, CAR design must strive not only for high potency and HIV specificity, but also to approach the ideal qualities of inescapablilty and non-immunogenicity. Our strategy involves bispecific targeting domains consisting of an extracellular region of human CD4, the primary HIV receptor, attached to a second motif that recognizes a distinct highly conserved region on the otherwise highly variable Env. The second motif is intended both to enhance CAR potency, and to prevent the CD4 from acting as an HIV entry receptor on CAR-expressing CD8+ T cells. We have focused on second motifs predicted to lack the immunogenicity associated with antibody-based CARs. A particularly favorable construct contains CD4 linked to the carbohydrate recognition domain of human mannose-binding lectin (MBL), which recognizes the highly conserved oligomannose patch on gp120 (Ghanem et al., Cytotherapy). In another variant, CD4 is linked to the N-terminal portion of the CCR5 co-receptor. We found that the bispecific CARs broadly suppressed infection by genetically diverse HIV-1 isolates, with significantly greater potency than a monospecifc CD4 CAR. Similar results were obtained using rhesus macaque PBMCs and a rhesus version of the CD4-MBL CAR. These results set the stage for testing the activities of the CD4-based bispecific CARs in relevant animal models including rhesus macaques and humanized mice.
Efficacy of immunotherapy approaches in metastatic and non-metastatic lung cancer models
Authors: Bommireddy Ramireddy , Menon Ashwathi P. , Munoz Luis E. , Huang Lei , Kim Janet , Kumar Jay , Lakshmanan Ramana , Ramalingam Suresh S. , Selvaraj Periasamy 
Published: January 2023

Abstract
Lung cancer is the leading cause of cancer related deaths accounting for approximately 30% of all cancer related mortalities affecting both men and women. Currently, there is no cure for the common non-small cell lung cancer (NSCLC) thus development of efficacious therapies is urgently needed. In this study, we investigate the efficacy of tumor membrane-based vaccine immunotherapy and immune checkpoint blockade antibodies in an aggressive, non-metastatic, immune checkpoint inhibitor resistant lung cancer model (LL/2) and a highly metastatic lung cancer (CMT-167) model. LL/2 and CMT-167 tumor tissues were harvested from C57BL/6 mice and processed to generate tumor membrane vesicles (TMVs). TMVs were then mixed with adjuvants and used for immunization in conjunction with immune checkpoint inhibitors. Tumor growth was monitored every 3 days. Survival was assessed using a Kaplan-Meier survival curve and significance determined using a Log-rank test for comparison analysis. Metastasis of CMT-167 was assessed by clonogenic assay. TMV alone, or in combination with adjuvants, anti-PD-1 or anti-CTLA-4 antibodies neither decreased the tumor growth nor improved the survival of mice challenged with LL/2 tumor cells. However, anti-PD-1 antibody delayed the tumor growth, improved the survival and reduced pulmonary metastasis in mice challenged with CMT-167 tumor cells. These models provide a valuable tool in analyzing the mechanism of interaction of immune cells with tumors that lead to either tumor regression or resistance to immunotherapies.
Potentiating effects of high-molecular weight fucoidan-agaricus mix (CUA) feeding on tumor vaccination
Authors: Miyazaki Yoshiyuki , Iwaihara Yuri , Nakamizo Masaji , Takeuchi Shugo , Takeuchi Hideaki , Tachikawa Daisuke 
Published: January 2023

Abstract
Fucoidan is a series of sulfated polysaccharides derived from brown algae that mainly consist of L-fucose. Various biological activities of fucoidan such as anti-cancer and immune modulatory effects were reported, and our investigation with animal experiments and human trials demonstrated fucoidan from Cladosiphon okamuranus and Undaria pinnatifida effectively augmented anti-tumor immunity in combination with Agaricus blazei mycelium extract. In this study, we evaluated dietary effects of the two types of high-molecular weight fucoidans and the agaricus extract mix (CUA) on achievement of effective tumor vaccination with a tumor antigen gp70 expressed on colon-26 tumor cell line. Balb/c mice were immunized with 0.05 mg gp70 peptide emulsified in complete freund’s adjuvant and intake 1% CUA containing AIN93G diet for 4 weeks. This procedure totally enhanced systemic immune function because splenocytes from the vaccinated mice extensively proliferate in response to concanavalin A-stimulation. The NK cell activity and gp70 peptide-stimulated IFN-gamma production in splenocytes from the vaccinated mice were tended to augment by the CUA feeding. On the other hands, the CUA feeding potentiated the killing activity to colon-26 carcinoma of draining lymph node (LN) cells from the vaccinated mice in association with increase of gp70-specific CD8-positive T cell population. Furthermore, the expressions of MHC class II molecule (I-A/I-E) on CD11c-positive and F4/80-positive populations of LN cells from the vaccinated mice were elevated by the intake of CUA. These results suggested that the CUA feeding potentially support effective induction of anti-tumor immune function by vaccination with tumor antigen peptides.