bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prostate epithelial cell intrinsic C3 represses MYC-driven tumorigenesis
Authors: Kunz Natalia , Bobby Jack , Yamamoto Hidekazu , Merle Nicolas , Wang Luopin , Taj Md , Ma Jianping , Kolev Martin , Loetscher Jonas , Kellerhals Tamara , Balmer Maria , Chandra Ash , Hess Christoph , Afzali Behdad , Kazemian Majid , Dasgupta Prokar , West Erin 
Published: November 2024

Abstract
The synthesis of complement component C3 within the tumor microenvironment has been implicated as a pivotal modulator in oncogenesis and is emerging as an attractive therapeutic target. Historically, tumor-infiltrating immune cells have been recognized as principal contributors to intra-tumoral C3, with resultant activation fragments primarily facilitating tumor progression via immunosuppression and induction of angiogenesis. Despite the ubiquity of C3 expression in neoplastic tissues, the implications of cancer cell autonomous C3 during oncogenesis remain inadequately characterized. Here we show that loss of steady-state, endogenous C3 expression, C3a generation, and C3a receptor engagement in human prostate epithelial cells (PECs) mark a salient transition towards malignancy. We reveal that tonic intrinsic C3a-C3aR engagement in non-transformed PECs serves to restrain phosphoinositide 3-kinase delta activity, which inhibits the oncogenic MYC cascade and MYC-driven ribosomal biogenesis and nucleolar dynamics to maintain normal cell homeostasis. Further, comprehensive analyses show that C3 transcript and C3 protein levels are widely suppressed across human prostate cancers. Collectively, these findings ascribe a non-traditional, tumor-suppressor function to cell intrinsic C3 and advocate for dissection of the context-specific roles of complement, a strategy that may inform the development of targeted cancer therapies.
Endometrial stromal cells define the fate of decidual Dendritic Cells through endoplasmic reticulum stress transmission
Authors: Gori Soledad , Schafir Ana , Soczewski Elizabeth , Grasso Esteban , Fernández Laura , Grassi Bassino Alejandra , Blejer Jorgelina , Vota Daiana , Pérez Leirós Claudia , Ramhorst Rosanna 
Published: November 2024

Abstract
Endometrial stromal cells acquire a secretory profile associated with a physiological endoplasmic reticulum stress (ERS) and the onset of a sterile inflammatory response to sustain embryo implantation. Here we evaluated the impact of endometrial stromal cells on Dendritic Cells (DC) differentiation through ERS-transmission. We used an in vitro model based on differentiated-monocytes from healthy women (with rhGM-CSF+rhIL-4) cultured in the absence/presence of Conditioned Media (CM) from stressed Human Endometrial Stromal Cells (HESC stimulated with Thapsigargin). Those DC cultures differentiated with stressed-HESC showed a lower frequency of CD1a+CD14- accompanied by an increased CD86high cell-population and higher COX2 expression. We also detected an increase in IL-1β secretion and in AnnexinV+/PI+ cell-population, indicating a lytic programmed cell death. The ERS-transmission was confirmed by increased IRE1α expression on DC. In fact, IRE1α inhibitor prevented the conditioning to a pro-inflammatory DC profile. Finally, to investigate the impact of the DC-inflammatory profile on blastocyst implantation ability, we tested trophoblastic spheroids migration. Blastocyst-like spheroids displayed an altered trophoblast migration when were cultured with supernatant from stressed-DC. These results suggest that ERS might be transmitted from stromal cells to DC and its fine balance is required to maintain tolerance for successful embryo implantation and trophoblast migration.
Molecular mechanism of activation of human cardiac fibroblasts during Pseudomonas aeruginosa infection
Authors: Ellendula Maneeth , Planner Clara , Kumar Naresh , Thomas Alison , Salam Sameerul , Lafuse William , Collins Patrick , Wozniak Daniel , Rajaram Murugesan 
Published: November 2024

Abstract
The prevalence of cardiac dysfunction and its vast implications for human health highlight the need to investigate the mechanistic processes allowing its pathological manifestations. Studies from our lab revealed Pseudomonas aeruginosa (P.a.) infection causes severe cardiac inflammation and dysfunction, despite absence of the bacteria in the heart. However, the underlying mechanism is unknown. Thus, we hypothesize cardiac fibroblast activation by PAMPs enhances cytokine and chemokine release, driving cardiac inflammation. To test our hypothesis in vitro, we used human monocyte derived macrophages (hMDMs) and cardiac fibroblasts (HCFs). We harvested conditioned media (CM) from P.a. infected hMDMs and exposed to HCFs. RNA was extracted at different time points, next generation mRNA sequencing was performed and supernatants were harvested to determine inflammatory cytokine. Our data revealed exposing CM to HCFs upregulates cytokine and chemokine gene expression. Also, we found CCL2, TNF-α and IL-1β levels are high in supernatants harvested from HCFs. To further investigate mechanisms controlling CCL2 expression in HCFs, we identified JNK was involved in induction of CCL2 in HCF. In conclusion, activation of HCFs releases chemokines (CCL2) which recruit leukocytes into heart tissue, causing severe cardiac inflammation. Ongoing and future studies are needed to dive further into mechanisms of this pathway, showing its potential impact in driving cardiac inflammation in vivo.
Exploring the Impact of Escherichia coli TcpC, a Bacterial TIR Domain-Containing Protein, Using Planaria and Dictyostelium discoideum as Model Organisms.
Authors: Akingbehin Victoria , Snyder Michelle 
Published: November 2024

Abstract
An estimated 1.2 million individuals lose their lives each year due to antibiotic-resistant bacterial infections, surpassing the mortality caused by HIV/AIDS or malaria. Uropathogenic Escherichia coli (UPEC) is among the most common causative agents of urinary tract infections (UTIs). UPECs survive in hosts using various mechanisms, including by secreting a protein known as TcpC. TcpC is a Toll-like/interleukin-1 receptor (TIR) domain-containing protein that modifies mammalian innate immunity by inhibiting the host Toll-like receptor (TLR) response. We hypothesize that TcpC also affects the survival of UPECs in model systems, including the social amoeba Dictyostelium discoideum and planaria flatworms. To test this hypothesis, we are using mutant strains of the UPEC CFTO73 that have altered expression of TcpC to analyze the effects of TcpC on bacterial growth and virulence in these model organisms. Our initial tests with D. discoideum indicate that the presence of TcpC in UPEC strains may increase their resistance to grazing and phagocytosis by the social amoeba D. discoideum. We are currently testing the effects of TcpC on survival of UPEC strains in planaria. If TcpC affects survival of UPECs in these model systems, this may open new avenues for characterization of the molecular mechanisms used by bacterial TIR domains to evade mammalian innate immune cells.
Understanding variant-specific variations in neutrophil functional kinetics associated with SARS-CoV-2 infection in a feline animal model
Authors: Gunasekara Sachithra , Shatnawi Shoroq , Ludwig Breya , More Sunil , Miller Craig , Rudd Jennifer 
Published: November 2024

Abstract
The intricate interplay between neutrophils and diverse SARS-CoV-2 variants offers insights into immunopathogenesis and potential therapeutic interventions in SARS-CoV-2 infection. Utilizing our COVID-19 feline model, we hypothesize that neutrophil dysregulation and the release of neutrophil extracellular traps (NETs) are highly strain-dependent in domestic cats. Specific-pathogen-free cats (n=8) were inoculated with SARS-CoV-2 (n=3 B.1.617.2/Delta; n=3 XBB.1.5/Omicron) or vehicle (n=2). Plasma, bronchoalveolar lavage, and lung tissues were collected over 5 days. Flow cytometric analysis of neutrophil subsets in blood, BAL, and tissues revealed functional and phenotypic changes (CXCR2+CXCR4-CCR5+) in Delta vs. Omicron vs. vehicle. Detection of NETs using MPO-DNA ELISA indicates significant elevations at 4dpi and 5dpi in the plasma and BAL of Delta and Omicron cats when compared to vehicle. Multiplex immunoassay conducted on BAL revealed significant elevation of pro-inflammatory cytokines including TNF-α, IL-8, and IL-18 in infected cats compared to vehicle favoring delta strain. RT-PCR and western blot on lung tissues utilizing three major markers of activated neutrophils and NETS (citrullinated histone 3, MPO, and neutrophil elastase) show marked expression in Delta cats vs Omicron and vehicle. These findings underscore the versatility of domestic cats as a translational model for developing targeted interventions based on variant-dependent neutrophil population dynamics.
Roles for the chemokine receptor CCR6 in pancreatitis and pancreas cancer
Authors: Drouillard Donovan , Volkman Brian , Dwinell Michael 
Published: November 2024

Abstract
Pancreatic ductal adenocarcinoma (PDAC) has a poor average life expectancy of ten months, in large part due to the immunosuppression surrounding the tumor preventing effective anti-tumor immune responses. A mediator of PDAC immunosuppression is regulatory T cells (Tregs). Conversely, pancreatitis is an inflammatory disease and is the leading risk factor for developing PDAC yet is lacking in Tregs. My preliminary data show that CCR6+ Th17 T cells are enriched in pancreatitis, while CCR6+ Tregs are enriched within PDAC tumors with little Th17s. Comparison of CCR6+ Tregs to CCR6- Tregs in PDAC show upregulation of genes involved in activation and suppressive function in the CCR6+ population with reliance on the RORyt and RORA transcription factors. The data suggest that CCR6+ Tregs possess superior suppressive capability and are derived from Th17s. The only ligand for CCR6 is CCL20, which is upregulated in both pancreatitis and PDAC and is correlated with a worse prognosis in PDAC. In pancreatitis, CCL20 is produced by Th17s and macrophages, while in PDAC the CCL20 is produced largely by the basal subtype of PDAC tumor cells. Using mouse models of PDAC, we demonstrated that knock-out of CCR6 resulted in beneficial increase of anti-tumorigenic immune populations within PDAC tumors. Cumulatively, these data support the notion that CCR6 is viable as both a treatment for pancreatitis and as an adjuvant to improve the efficacy of immunotherapy in PDAC.
Endogenous ICOS signaling supports Th17 therapy efficacy
Authors: Wittling Megen , Knochelmann Hannah , Cole Anna , Wyatt Megan , Ruffin Ayana , Kumarasan Soundharya , Bennett Frances , Swisher Shannon , Paulos Chrystal , Lesinski Gregory 
Published: November 2024

Abstract
Objective: We sought to determine the mechanism by which antigen-specific Th17 cells are able to clear melanoma tumors more effectively than their Th1 counterparts and to expand on the role of ICOS in the success of Th17 therapy.
Methods: Antigen-specific TRP-1 CD4+ T cells were polarized to Th17 or Th1 phenotypes and were adoptively transferred into mice bearing B16F10 melanoma. The role of inducible costimulatory molecule (ICOS) in this therapy response was evaluated by antibody blockade and genetic deletion. RNA-Sequencing, flow cytometry, and tumor growth measurements were additionally used to assess differences when ICOS was blocked or not.
Summary of Results: ICOS is important for the efficacy of Th17 therapy in mice with established melanoma as when blocking ICOS signaling via antibody or genetic means, both antitumor activity and survival was diminished. By assessing the phenotype of both infused and host lymphocytes, we found that B cell proliferation and the engraftment of transferred cells decreased in the mice blocked of ICOS signaling. I also found that ICOS signaling appears to be important early on after Th17 cells infusion, as blocking ICOS at early but not later time points compromised antitumor immunity.
Conclusions: ICOS is important for long-term survival and antitumor activity of mice treated with Th17 cells targeting melanoma.
Restoring NAD+ levels sensitize checkpoint resistant tumors to PD-1 therapy mediated through macrophage-NK-T cell crosstalk.
Authors: Chakraborty Paramita , Chatterjee Shilpak , Subramanian Suganya , Parikh Rasesh , Hedley Zacharia , Vaena Silvia , Romeo Martin , Schooten Wim , Gangaraju Vamsi , Berto Stefano , Mehrotra Shikhar 
Published: November 2024

Abstract
Immune checkpoint blockade therapy (ICB) often targets tumoricidal capacities of T cells. However, innate immune cells present in the tumor microenvironment (TME) play a decisive role in the efficacy of ICB. Therefore, developing combination therapies that target multiple immune populations is of considerable interest. Nicotinamide adenine dinucleotide (NAD+), the crucial metabolic intermediate, acts as a cofactor in redox processes and co-substrate for multiple enzymes. Immune populations in TME express surface CD38, a NAD hydrolase that reduces the tissue NAD+ levels, impairing T cells metabolic fitness. Here we used an antibody that blocks the NAD hydrolase activity of CD38 and is non-toxic in vivo, as compared to the commercially available anti-CD38 antibody (NIMR5), that relies upon antibody-dependent cellular cytotoxicity (ADCC). We found that combined therapy with αPD-1 and αCD38 antibody significantly enhances tumor control in PD-1-resistant melanoma model. Single-cell RNA sequencing, flowcytometry analysis and cell depletion studies revealed that combination therapy leads to transcriptional reprogramming of macrophages, improves macrophage-NK-T cell crosstalk, and facilitates immune infiltration in the TME. These results highlight the importance of boosting the TME's NAD+ level in conjunction with ICB and allude to the potential of an improved endogenous immune response against cancers that are resistant to checkpoint treatment and typically regarded as incurable.
Lung homeostasis is maintained by the interactions between CX3CR1-expressing interstitial macrophage and lung commensal bacteria.
Authors: Kim Kiwook , Kim Seung Hyeon , White Zachary , Gainulina Anastasiia , Kim Jiseon , Dominguez Joseph , Kang Soeun , Hay Nissim , Chevrier Nicholas , Gunzer Matthias , Sano Teruyuki 
Published: November 2024

Abstract
As an anti-inflammatory cytokine, IL10 plays an important role in modulating immune responses. However, it remains relatively unknown about the importance of IL10-IL10 receptor (IL10R) signaling in maintaining lung homeostasis. Here we investigated that IL10R signaling of lung interstitial macrophages (IMs) contributes to the maintenance of tissue homeostasis by preventing fibrosing lung inflammation. We observed that IL10-deficient mice spontaneously induced lung inflammation in adulthood. In parallel, IL10R-deficiency of IMs identically induced the inflammatory phenotypes observed in IL10-deficient mice. Antibiotics treatments, 16S rRNA-Sequencing analysis, and germ-free (GF) animals allowed us to determine that the lung inflammation occurring in the absence of IL10 or IL10R was triggered by lung commensal dysbiosis. Furthermore, we identified that two distinct commensal microbes (D. Acidovorans and R. Erythropolis) dominantly colonized in the lung of mice lacking IL10R in IMs, where these commensals initiate lung inflammation. Collectively, our data highlight that IL10R signaling of IMs contributes to lung homeostasis by restricting commensal dysbiosis and prevents progressive lung fibrosis.
Identification and characterization of PD-1 agonists for the treatment of autoimmune and inflammatory diseases
Authors: Ramello Maria , Grebinoski Stephanie , Panduro-Sicheva Marisella , Borah Minasri , Vitlip Joshua , Lutz Stephen , Cianci Michael , Ramello Maria , Sharma Ishan , Wittenberg Elliott , Colthart Allison , Visweswaraiah Jyothsna , Higginson-Scott Nathan , Otipoby Kevin , Cipolletta Daniela 
Published: November 2024

Abstract
The development of autoimmune diseases is the result of a dysregulated immune response against self-antigens, resulting in cell dysregulation and tissue damage. Upon chronic exposure to antigens, inhibitory receptors (IR) are upregulated as a feedback mechanism to limit T-cell effector activity. IR deficiency is associated with autoimmunity in mice and humans. Similarly, blockade of IR is efficacious for the treatment of cancer but is often associated with new onset of immune-related adverse events. Therefore, if loss or blocking of IR pathways can result in autoimmunity, agonism of these pathways should restore normal immune homeostasis. However, the generation of agonistic antibodies present some challenges. For instance, to elicit strong receptor agonism, super-clustering mediated by the binding of the constant region (Fc) of an antibody to FcgRs, must occur. However, while FcgRs are widely expressed on antigen-presenting cells (APCs), they are not the same and are classified, based on their function, as activating or inhibitory. Of note, FcgRIIb is the only inhibitory Fc receptor, and APCs derived from mice deficient in this receptor exhibited exaggerated cytokine release. Most PD-1 agonist antibodies in clinical development contain a wild-type Fc and can trigger unwanted production of pro-inflammatory cytokines by engaging activating FcgRs. To mitigate such liability, we designed novel PD-1 agonistic antibodies that selectively bind FcgRIIb and prevent APC activation.
Fusion of Antigen with Efferocytic Mediators Induces Antigen-Specific Tolerance and Reduces Allergic Airway Inflammation in Mice
Authors: Reda Joseph , Budina Erica , Medellin Emiliano , Foley Colleen , Garza Camryn , Ung Trevor , Chang Kevin , Wang Thomas , Hubbell Jeffrey 
Published: November 2024

Abstract
We made proteins that combine efferocytic mediators, which help clear dying cells, and ovalbumin (OVA), a model antigen. We demonstrate that these fusions maintain affinity to their membrane target, phosphatidylserine, and enhance uptake by murine dendritic cells in vitro. Furthermore, we found that antigen-pulsed DCs were capable of driving proliferation of both cognate CD4+ and CD8+ T cells, demonstrating evidence of antigen degradation and presentation. Similar observations were made following adoptive transfer of OVA-specific T cells into naive mice, in which the T cells demonstrated dampened recovery and effector function. Finally, we explored GAS6-OVA, one of the biologics described in this work, in the context of an allergic airway inflammation model in mice. After being treated prophylactically with GAS6-OVA, mice demonstrated lesser eosinophilia in bronchealveolar lavage fluid and lesser mucus hypersecretion as assessed by histology following challenge with OVA. These results suggest that our proteins can induce tolerance to a specific antigen, which may be useful for diseases caused by an abnormal immune response to a known antigen. Future work will explore the potential of our proteins to treat these diseases, to induce tolerance to other antigens, and to modulate immune responses in the context of an antigen-experience immune system.
IL-6 receptor blockade prevents polarization of pro-fibrotic macrophages in myeloid-rich RA synovial tissue
Authors: Mantel Ian , Singaraju Anvita , Townsend Hope , Lakhanpal Amit , Zhang Fan , Donlin Laura 
Published: November 2024

Abstract
In rheumatoid arthritis (RA), macrophages represent key therapeutic targets due to their ability to drive inflammation. Interestingly, new subtypes of RA have been identified, based on distinct patterns of cell types in the joint, wherein one-third of patients demonstrate an enrichment of pro-fibrotic SPP1hiCLEC5Ahi macrophages. We set out to understand what drives the formation of these macrophages in RA joints, and how anti-inflammatory medications used to treat RA may differentially affect joints with pro-fibrotic versus pro-inflammatory macrophages. In RA joints with an abundance of SPP1hiCLEC5A+ macrophages, TGFB1 expressing endothelial cells and stromal cells expressing IL6 and CSF1 are co-enriched. In an in vitro culture system, we found that the SPP1hiCLEC5A+ macrophage phenotype could result from exposure to factors from synovial fibroblasts along with TGF-β. Blockade of the IL-6 receptor with tocilizumab inhibited the generation of the fibroblast-directed SPP1hiCLEC5A+ macrophage state. This differed from the inflammatory HBEGF+IL1B+ macrophage state, found in joints with extensive T and B cell aggregates. Interestingly, in a clinical trial that used tocilizumab, joint tissue transcriptomics demonstrated a reduction in SPP1hiCLEC5A+ cell signatures. This study highlights the importance of making treatment decisions for RA patients informed by the cellular composition of the affected tissue.
Adjuvanticity of ISA51 and ISA720 in the induction of immune tolerance
Authors: Mone Kiruthiga , Rasquinha Mahima , Sur Meghna , Steffen David , Reddy Jay 
Published: November 2024

Abstract
Various immune suppressive therapies have been used to treat autoimmune diseases, and the risks of immune suppressants can be mitigated using strategies that promote antigen-specific tolerance. Here, we report the utility of ISA51 and ISA720, a new generation of water-in-oil adjuvants in the induction of tolerance to proteolipid protein 139-151 (PLP) using the mouse model of experimental autoimmune encephalomyelitis (EAE) for multiple sclerosis. First, emulsions of ISA51 or ISA720 containing PLP 139-151 induced robust T-cell responses comparable to the complete Freund’s adjuvant (CFA)/PLP 139-151 group. Second, CFA/PLP 139-151, but not ISA51 or ISA720 emulsions induced EAE in SJL mice. Third, while splenocytes from the CFA/PLP 139-151 group produced IFN-γ, TNF-α, and IL-6, cells from ISA 51 or ISA720 groups had predominant production of IL-5, IL-9, and IL-22, but levels of IL-17A and IL-17F were comparable. However, if any, IL-4 and IL-10 levels were high in the CFA/PLP 139-151 group. Conversely, cytokines of lymph node cultures revealed high amounts of IFN-γ, IL-9, IL-10, IL-17A, IL-17F, IL-22, TNF-α, and IL-6 in the CFA/PLP 139-151 group relative to others. Strikingly, IL-5, IL-9, IL-17A, IL-17F, and IL-22 levels were elevated in ISA720/PLP 139-151 group as compared to ISA51/PLP 139-151 group. The data suggest that T cell tolerance can be induced with self-antigens emulsified in ISA51 or ISA720 independent of cytokines produced by specific T helper subsets.
CD4+ T cell lymphopenia decreases survival in older adults with glioblastoma
Authors: Zhai Lijie , Penco-Campillo Manon , Lauing Kristen , Wainwright Derek 
Published: November 2024

Abstract
OBJECTIVE: Glioblastoma (GBM) is the most common and aggressive primary brain tumor with a median age of onset at ~70 years of age. GBM patients ≥ 65 years of age have worse survival outcomes than younger counterparts (p&lt;0.0001). Older human GBM patients with CD4+ lymphopenia show decreased survival as compared to age-matched GBM controls (p&lt;0.05). Here, we evaluated the effects of tumor and various forms of lymphopenia in young and old mice with GBM. METHODS: Young 6-12 weeks of age or old ≥80-120 weeks of age C57BL/6 mice were treated with either IgG isotype control antibodies or with depleting antibodies against murine CD4, CD8, or NK1.1 beginning at 3 days prior to- and every 3 days post-intracranial injection of the syngeneic GBM cell lines, GL261, CT-2A, or SB28. Overall survival was compared between groups. RESULTS: Older adult mice, but not younger mice, with either intracranial GL261, CT-2A, or SB28 cell-based brain tumors have a significantly decreased overall survival when depleted for CD4+ T cells as compared to the IgG control-treated group or groups depleted for CD8+ T- or NK-cells (p&lt;0.05). Based on the precipitous decline in overall survival due to CD4+ T cell lymphopenia, a tumor-independent effect is suspected. CONCLUSIONS: The data suggest that CD4+ T cells play a more sophisticated role in maintaining the survival of older adult subjects with GBM than in the younger subjects and that their contribution goes beyond an anti-tumor-only contribution.