bluuebunny/crossref_metadata_2025_split huggingface dataset:
Immunostimulatory effects of nanosecond pulsed electric fields
Authors: Muratori Claudia , Mazzarda Flavia , Chittams-Miles Alexandra , Vernier P Thomas 
Published: August 2023

Abstract
Intense pulsed electric fields (PEF) are increasingly employed for tumor ablation, including inoperable tumors, bleeding metastases, and tumors unresponsive to alternative treatments. PEF disrupt the membrane barrier of tumor cells leading to irreversible changes in homeostasis and cell death. Using different tumor models, we found that treatment with nanosecond duration pulsed electric fields (nsPEF) enhance the host antitumor immune response. The strongest effect was measured in mice bearing CT26 colon carcinoma tumors where the local treatment with nsPEF protected 78% of the animals from a second tumor cell challenge. We hypothesize that nsPEF-treated tumors act as an in-situ cancer vaccine by initiating innate immunity while molding and sustaining adaptive immunity. Indeed, we provide evidence that the damage created by these short electrical stimuli is sensed by the innate immune platform known as inflammasome. Upon assembly, the inflammasome induces proinflammatory cytokine processing and a form of cell death known as pyroptosis. We found that nsPEF triggered pyroptosis in macrophages accompanied by caspase-1 activation and release of IL-1β. Concurrently, to sustain adaptive immunity, nsPEF in tumor cells activate persistent ER-stress accompanied by phosphorylation of translation initiation factor 2α (eIF2α): a biomarker of immunogenic cell death. Tumor antigen-release from nsPEF-treated tumor cells comes with the release of damage-associated molecular patterns such as ATP, HMGB1 and calreticulin. Understanding and manipulating the cross talk between innate and adaptive immunity after nsPEF is expected to improve the immunotherapeutic response triggered by these treatments.
Pulse Biosciences, Inc.
Heterologous prime-boost viral vector cancer vaccines have protective effects against a syngeneic mouse model of glioblastoma
Authors: Steffke Emily E , Noblecourt Laurine , Almeida Vinnycius Pereira , Wicki Amanda , McAuliffe James , Kohanbash Gary , Okada Hideho , Leung Carol , Terabe Masaki , Van den Eynde Benoit 
Published: August 2023

Abstract
Glioblastomas are immunologically “cold” tumors with intense immunosuppressive myeloid cell- and sparse cytotoxic T-cell infiltration. Therefore, viral vector vaccines may be a promising approach to boost the induction of glioblastoma-targeted T cells. It has been previously shown that heterologous prime-boost vaccination with chimpanzee-derived adenovirus ChAdOx1 and modified vaccinia Ankara (MVA) vectors can induce a high magnitude of CD8+ T cells specific for cancer-associated antigens and have therapeutic effects against mouse models of cancer. Therefore, we aimed to evaluate whether using ChAdOx1 and MVA vaccines targeting model antigen P1A, a mouse equivalent to human tumor-associated Melanoma Antigen GenE (MAGE)-type antigens, could have protective effects against a P1A-transfected BGL-1 glioblastoma model. Mice were vaccinated with ChAdOx1/MVA-P1A vaccines, then challenged subcutaneously with P1A-expressing BGL-1 cells. Prophylactic vaccination with ChAdOx1/MVA-P1A significantly prolonged the survival of syngeneic mice subcutaneously challenged with P1A-expressing BGL-1 tumors. Furthermore, different vaccination schedules significantly impacted the magnitude of antigen-specific CD8+ T-cell responses and protective efficacy. Future studies will investigate the protective effects of vaccination against intracranial P1A-expressing BGl-1 tumors.
Supported by grants from the Ludwig Institute for Cancer Research, University of Oxford; the NIH Intramural Program (ZIA BC011877), the NIH Oxford-Cambridge Scholars Program, and the Marshall Scholarship Program.
Depletion of Polymorphonuclear Myeloid-Derived Suppressor Cells Increases Efficacy of Listeria monocytogenes Cancer Vaccine
Authors: Williams Jacob E , Castillo Jesse Garcia , Fernandez Sebastian , Portnoy Daniel A , DuPage Michel 
Published: August 2023

Abstract
The tumor microenvironment is highly immunosuppressive, allowing cancer to evade the immune system by inducing the dysfunction, exhaustion, or subversion of CD8+ T-cell functions. Cancer immunotherapies using attenuated strains of Listeria monocytogenes (Listeria) engineered to express tumor antigens have been demonstrated to promote cancer antigen-specific CD8+ T-cells that infiltrate the tumor microenvironment and control mouse models of cancer. However, in human clinical trials, initial IV therapies utilizing Listeria did not demonstrate strong clinical efficacy, suggesting that the generation of tumor-specific CD8+ T-cells recognizing tumor antigens alone is insufficient to provide robust tumor control. Here, we demonstrate that intratumoral (IT) or intravenous (IV) inoculation of an attenuated form of Listeria(ΔActA) demonstrated no therapeutic benefit in the context of establish MC38 tumor-bearing mice while predominantly recruiting and infecting CD11b+Ly6G+CD14+ cells in the tumor microenvironment, markers associated with polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs). In vitro analysis of PMN-MDSC infection by Listeria revealed increased immunosuppressive function, indicating a possible adverse outcome of Listeria treatment in vivo. Further, IV or IT injection of Listeria in the context of PMN-MDSC depletion increased the therapeutic efficacy of Listeria therapy and promoted a robust CD8+ T-cell mediated anti-tumor response. Collectively, our results demonstrate that depletion of PMN-MDSCs may be required to mediate the therapeutic efficacy of Listeria inoculation in the context of cancer immunotherapy and the production of an effective anti-tumor immune response.
Supported by grants from NIH (DP2CA247830) & Cancer Research Coordinating Committee (CRCC) (C23CR5612)
Systemic Cancer Immunostimulatory Therapies and Acute Viral Infection Induce Corticosteroid-Mediated Thymic Involution and Naïve T cell Output in Mice and Humans
Authors: Yoon Daniel J , Khuat Lam Tan , Collins Craig , Vick Logan , Sckisel Gail , Minnar Christine Mall , Dunai Cordelia , Curti Brendan , Chao Nelson J , Blazar Bruce , Longo Dan L , Canter Robert , Monjazeb Arta , Murphy William J 
Published: August 2023

Abstract
Thymic involution (TI) occurs with aging and during stress responses, decreasing naïve T cell output. Thymic progenitor apoptosis can occur directly by corticosteroids (CS) leading to transient involution followed by recovery. The effects of systemic immunotherapies (IT) used in cancer or immune stimulation via acute viral infection on the thymus has not been well-characterized and was the primary goal of this study. IT treatment of mice with high dose IL-2 (HD IL-2) or models of acute viral infection (mouse cytomegalovirus, MCMV) all resulted in rapid TI due to apoptosis of CD4/CD8 double-positive progenitors followed with a reduction in naïve T cell content. Interestingly, cessation of therapy or resolution of viral infection resulted in greater thymic size compared to untreated recipients, indicating a rebound effect. In both models, increased CS levels in the serum of mice preceded TI. Clinically, patients receiving HD IL-2 for cancer had significantly reduced T cell receptor excision circles, a marker for naïve T cell output, also correlating with increased cortisol levels. Using a model of sub-lethal MCMV infection that did not increase systemic pro-inflammatory cytokines, we observed a similar correlation of TI and increased CS levels. To further analyze the effects of CS on TI, mice were adrenalectomized and then given HD IL-2, where significantly reduced CS levels correlated with partial protection from TI. These results indicate that strong systemic immunostimulation by either IT or acute viral infections markedly induce transient CS-mediated TI, leading to a decrease in naïve T cells. Therefore, targeting CS responses in preventing TI and, especially with the aged, allow for naïve T cell populations to be maintained.
Mucosal vaccination with an adenoviral vector vaccine protects against pulmonary breast cancer metastasis by robust induction of tissue-resident memory T-cells in the lung
Authors: Oltmanns Friederike Elise , Antão Ana Vieira , Irrgang Pascal , Schmidt Anna , Viherlehto Vera , Jörg Leticia , Tenbusch Matthias , Lapuente Dennis 
Published: August 2023

Abstract
The presence of tissue-resident memory T-cells (TRM) in solid tumors positively correlates with an improved overall prognosis and responsiveness to checkpoint inhibitor therapy. Rationally designed vaccine approaches capable of inducing antitumor TRM at cancer sites are needed to harness the full potential of localized immunity in tumor therapy. Our project aims to establish tumor antigen-specific lung TRM by mucosal vaccination with an adenoviral (Ad) vaccine to prevent and treat lung metastasis in the murine 4T1 breast cancer model.
We employ Ad serotype 5 vectors encoding for 4T1 tumor-associated antigens from Mage-b and MuLV gp70 for intranasal vaccination, supplemented with an Interleukin-1β-encoding vector to specifically boost lung TRM induction. Indeed, particularly if Ad-IL-1β was co-delivered, mucosal vaccination established high numbers of tumor antigen-specific CD69+CD103+ lung TRM as shown by phenotypic and functional analyses in combination with intravascular staining.
Vaccine efficacy was evaluated in a 4T1 pseudometastasis model mimicking a prophylactic vaccination against lung metastasis in breast cancer patients. Local immunization led to a significant protection against pulmonary metastasis and improved survival compared to non-vaccinated and, notably, intramuscularly immunized mice. By using FTY720 to inhibit T-cell circulation upon tumor challenge, we confirmed that TRM are crucial contributors to the vaccine efficacy.
In conclusion, induction of tumor-antigen specific lung TRM are a key point in local protection against pulmonary metastasis. Ongoing studies analyze the therapeutic use of this vaccination strategy as well as its potential in combination with immune checkpoint inhibition.
Supported by grants from ‘Anschubfinanzierung (ELAN) im IZKF’ and ‘Doktor Robert Pfleger-Stiftung’.
Targeting dendritic cell inhibitory receptors to down regulate immune response in inflammatory disease
Authors: Wei Hsi-Ju , Chen Liang , Patil Suresh , Barbon Jeffrey , Waire James , McCarthy Donna , Deora Arun , Laroux Stephen , Jin Liang , Tian Yu , Veldman Trudi , Ghayur Tariq , Hegde Subramanya 
Published: August 2023

Abstract
Immune regulator receptors play a crucial role in immune homeostasis by balancing activating vs inhibitory immune responses and are distributed across cells of myeloid and lymphoid lineages. Inhibitory receptors contain Immune Receptor Tyrosine-based Inhibitory Motifs (ITIM) and suppress immune response via SH2 domain-containing protein tyrosine phosphatases (SHP2). Dendritic Cell Inhibitory Receptor (DCIR) is a C-type lectin receptor expressed on monocytes, dendritic cells, and neutrophils. It has been implicated in controlling autoimmunity in preclinical models and polymorphisms linked to patients’ susceptibility to autoimmune diseases such as RA, Lupus, and Sjogren’s. Hence ligation of DCIR using monoclonal antibodies may provide inhibitory signals and therapeutic benefit. Here we show that agonistic anti-human DCIR antibodies (mAb) induce DCIR ITIM phosphorylation and SHP2 association. The DCIR/SHP2 complex diminished the SHP2 association of Syk with FcgR to inhibit TNFa, IL-1b, and IL-6 in human myeloid cells by attenuating the phosphorylation of SHP2, Syk, p38 and p65. Proteomic and RNAseq analyses also suggest that MAPK pathways are regulated by the agonistic mAbs. In human DCIR knock-in mice: (i) DCIR+ cells were enriched in inflamed crypts in DSS-induced colitis model; (ii) Agonistic mAbs reversed the weight loss and reduced the accumulation of neutrophils in the inflamed colon; (iii) Agonistic mAbs significantly reduced the recruitment of neutrophils and leukocytes in zymosanD-induced peritonitis model. Moreover, the increase of DCIR in activated neutrophils can be targeted by mAbs for their clearance. In summary, anti-DCIR agonistic mAbs modulate inhibitory functions and dampen inflammatory responses.
Class switched memory B cell development and transcriptional programming is regulated by EZH2
Authors: Wiggins Keenan J , Rose James , Boss Jeremy M , Scharer Christopher D 
Published: August 2023

Abstract
The most effective vaccines involve the development of antigen specific memory B cells (MBCs). MBCs make up a heterogenous population derived from germinal center (GC) dependent or independent processes, resulting in primarily immunoglobulin class switched and non-class switched MBCs, respectively. Class switched IgG MBCs are programmed to become plasma cells following a reinfection and non-class switched MBCs are programmed to seed secondary germinal centers. It is not clearly defined what epigenetic factors influence MBC differentiation and programming. EZH2 is a histone methyltransferase that catalyzes H3K27me3, resulting in gene repression. EZH2 has been shown to regulate multiple aspects of B cell differentiation, including development, germinal centers, and plasma cells; however, it is unknown if EZH2 regulates MBC development. To study EZH2, multiple knockout models have been established where EZH2 is conditionally deleted (cEZH2-KO). Here we used the influenza (PR8) model to determine the kinetics of antigen-specific MBC differentiation following a live infection in cEZH2-KO mice. We show that antigen positive MBCs are altered when EZH2 is deleted at days 14 and 39 post infection. Of the MBC subsets, IgG+, CD73+, and DP (PDL2+CD80+) MBCs were reliant on EZH2 for development but not IgM MBCs. These data indicate that extrafollicular/non-GC derived MBC differentiate in an EZH2-independent manner which reveals a distinct gene profile for extrafollicular/non-GC derived MBCs. EZH2 is necessary for repression of key gene regulators which determines the fate of class switched and non-switched MBCs. Overall, this model highlights the role of EZH2-dependent programming regarding MBC development and function.
Supported by R01 AI148471 from NIH/NIAID to CDS
The critical role of copper homeostasis during the immune response
Authors: Mandarano Alexandra H , McGargill Maureen A 
Published: August 2023

Abstract
Copper homeostasis is tightly regulated in living organisms, as copper is essential to numerous cellular processes but toxic in excess. Dysregulated copper homeostasis is associated with numerous human diseases, including genetic diseases of copper transport, cancer, autoimmune disease, and infection. Although patients with mutations in copper transporters have an increased susceptibility to infection, little is known about the changes in immune function in these diseases. Further, altering copper availability has shown promise in treating either autoimmunity or infection, but the mechanisms underlying this effect are unresolved. We examined serum copper levels in human samples during acute influenza or SARS-CoV-2 virus infections, revealing unique virus-dependent copper dynamics. As copper is required for important immune cell processes such as metabolism, signaling and maintenance of reactive oxygen species, we next investigated the effect of modulating copper levels on T cell activation. We found that copper chelation impaired T cell proliferation, reduced expression of T cell activation markers, and altered gene expression following stimulation. To determine the impact of copper levels during the immune response in vivo, we then treated mice with copper chelation prior to and during an influenza A virus infection. Notably, mice treated with copper chelation prior to infection had altered serum copper dynamics, greater weight loss, and more flu-specific T cells compared to untreated mice. Overall, our results demonstrate the importance of copper homeostasis during the immune response. Ongoing experiments will investigate the mechanisms underlying this role in immune function during disease.
Supported by ALSAC and NIH (5T32AI106700).
The interferon-rich skin environment regulates Langerhans cell ADAM17 to promote photosensitivity in lupus
Authors: Zyulina Victoria , Li Thomas M , Seltzer Ethan S , Dacic Marija , Chinenov Yurii , Daamen Andrea , Veiga Keila R , Schwartz Noa , Oliver David J , Lora Jose , Jabbari Ali , Liu Yong , Munir Hafsa , Shipman William D , Sandoval Marvin J , Sollohub Isabel F , Ambler William G , Mishra Bikash , Taber Sarah F , Onel Karen B , Zippin Jonathan , Rashighi Mehdi , Krueger James G , Anandasabapathy Niroshana , Rogatsky Inez , Blobel Carl P , Lipsky Peter E , Lu Theresa 
Published: August 2023

Abstract
Photosensitivity, a sensitivity to ultraviolet radiation, is a hallmark symptom of systemic and cutaneous lupus erythematosus (SLE and CLE). We have previously shown that photosensitivity in SLE models is caused by reduced function of Langerhans cells (LC) disintegrin and metalloprotease 17 (ADAM17), a sheddase that normally limits UVR-induced skin inflammation by activating epidermal growth factor receptor (EGFR) ligands. We also showed that LC ADAM17 activity is reduced in murine models and human SLE and that this LC ADAM17 dysfunction contributed to photosensitivity. The aim of this study is to understand why lupus LCs are dysfunctional and how type I interferon (IFN-I) in lupus skin contributes to LC ADAM17 dysregulation.
In this study we utilize multiple photosensitive SLE models and skin obtained from healthy human volunteers. LC ADAM17 activity and expression was measured by flow cytometry.
We found IFN-I signatures in non-lesional skin of MRL/lpr and B6.Sle1yaa photosensitive SLE models in addition to that of CLE patients, suggesting the similarities in gene expression patterns between human and mouse lupus skin. We also showed that IFN-I inhibits murine and human LC ADAM17 activity, and anti-IFNAR1 in SLE models restores LC ADAM17 function and reduces photosensitivity in EGFR− and LC ADAM17-dependent manners.
Together our findings suggest a model whereby the IFN-I-rich microenvironment in non-lesional lupus skin inhibits UVR-induced ADAM17 activity, leading to photosensitivity. These results suggest that the beneficial effects of the recently FDA-approved anifrolumab on human lupus skin may be attributable to effects on improving LC ADAM17 activity.
Foxp3 exon 2 regulates keratinocyte-specific IgE and basophil extracellular traps in cutaneous autoimmune photosensitivity
Authors: Domeier Phillip P , Stefani Caroline , Chen Shuting , Snyder Jessica M , Lacy-Hulbert Adam , Eisenbarth Stephanie C , Zhou Baohua , Ziegler Steven F 
Published: August 2023

Abstract
Ultraviolet B (UVB) light is a common environmental trigger that can induce flares in several autoimmune diseases, but the mechanisms that mediate UVB-induced photosensitivity remain poorly understood. We used mice which express an autoimmune-driving isoform of Foxp3, called FoxP3ΔE2 mice, to develop a model autoimmune cutaneous photosensitivity. In the steady-state, FoxP3ΔE2 mice have high serum titers of IgE that target skin-associated autoantigens, and increased numbers of IL4-producing T follicular helper cells that target skin-associated proteins (Keratin 14) in the absence of overt immune challenge. After skin exposure to UVB light, FoxP3ΔE2 mice had further elevated IgE, worsened skin inflammation, and increased IgE complex deposition that localized to the challenge site. IgE production in UVB-challenged mice correlated with increased frequencies of germinal center (GC) B cells, elevated percentages of IL-4+ T follicular helper cells, and numbers of basophils with high surface expression of IgE in the draining lymph nodes of UVB-challenged skin. We also observed a significant increase in IgE accumulation, increased numbers of Tug8+ basophil extracellular traps in UVB-challenged skin and increased frequencies of activated plasmacytoid dendritic cells (CD80+CD86+) in the skin and skin-draining lymph nodes of FoxP3ΔE2 mice when compared to wild-type littermates. Collectively, we found that T follicular regulatory cells in FoxP3ΔE2 mice fail to maintain self-tolerance in the GC, resulting in increased production of skin reactive IgE and worsened skin inflammation driven by basophil extracellular trap accumulation in UVB-damaged skin.
Supported by grants from the NIH (F32 AI154787, R01 AI136475, R21 AI169418, and R21 AI152444)
Paneth cells regulates innate lymphoid cells and B1 cells throughout the body
Authors: Joldrichsen Marisa R , Yoo Sungjun , Rayner Rachael , Cormet-Boyaka Estelle , Boyaka Prosper N 
Published: August 2023

Abstract
Paneth cells are a subset of small intestinal epithelial cells specialized to maintain gastrointestinal homeostasis through production of antimicrobial products and cytokines. The fact that dysbiosis has been associated with several noninfectious pathologies, has solidified the notion that Paneth cells contribute to the general health. However, little is known about Paneth cells beyond their role as regulator of the gut microbiota. Using mice lacking Paneth cells (Sox9ΔIEC mice), we now report that Paneth cells also regulate the composition of immune cell subsets in Gut-Associated Lymphoid Tissues (GALT) and but also in sites distant from the gut. Thus, loss of Paneth cells significantly decreased the number of ILC3s and increased the number of ILC2s in the intestinal lamina propria. Paneth cell deficiency also affected Peyer’s patches. In this regard, Paneth cell deficient mice displayed an increased numbers of Peyer’s patches which were of larger size than Peyer’s patches in control wild-type mice. Furthermore, Peyer’s patches of Paneth cell deficient mice contained increase numbers of IgA+CD19+B cells and B1a (CD19+CD5+) cells. Interestingly, when compared to control wild-type mice, the numbers of B1a cells were found to be also increased in mesenteric lymph nodes of Paneth cell deficient mice, but also at sites distant from the gut including the lungs, and bone marrow. Also, in the lungs there was an increase in ILC2s. Taken together, these findings indicate that Paneth cells play a key role as regulators of innate immune responses throughout the body via regulation of ILC subsets and B1 cells.
NIH Grants