bluuebunny/crossref_metadata_2025_split huggingface dataset:
The immune adaptor ADAP plays a pivotal role invariant natural killer T cell functions
Authors: Das Rupali , Gohl Trevor , Lee Hyun Hee , Mack Ryan , Abdelaziz Sami , Griffin Ryan 
Published: January 2023

Abstract
Invariant natural killer T cells (iNKTs) comprise a sub-lineage of T lymphocytes that express an “invariant” T cell receptor (TCR) with specificity for glycolipid antigens (Ag) such as a-galactosyl ceramide (aGC), when presented in complex with the MHC class I molecule CD1d. Following TCR engagement, iNKTs rapidly secrete cytokines and trans-activate the anti-tumor functions of dendritic cells (DC), natural killer (NK), T and B cells as well as directly kill tumor cells. Based on their dual functions as potent cytokine producers and tumor killers, iNKTs serve as a powerful tool for use in cell-based immunotherapies for cancer. Although TCR-CD1d interactions are generally required for iNKT cell functions, the signaling mechanisms that co-operate with the TCR to promote maximal iNKT cell responses remain poorly understood. Our previous studies demonstrate that the adaptor protein SAP and its signaling partner, Fyn (a Src-tyrosine kinase) is critical for iNKT cell functions. We recently investigated the role of ADAP (adhesion and degranulation promoting adaptor protein), a Fyn-binding protein in iNKT functions. We observe that aGC-induced iNKT cell activation, cytokine production, and bystander immune cell activation as well as anti-tumor response are remarkably reduced in ADAP-deficient (Adap−/−) mice. These data suggest that ADAP is a critical regulator of Ag-induced iNKT cell functions. Studies are currently underway to elucidate the mechanism(s) by which ADAP regulates iNKT cell functions. These studies will have an impact by establishing new paradigms for iNKT cell signaling and offering insights into how iNKTs can be best activated to enhance host immunity and treat cancer.
Suppressed plasmablast responses in febrile infants, including children with Kawasaki disease.
Authors: Hoffman Jonathon , Martin Meghan , Wrotniak Brian H. , Hicar Mark D. 
Published: January 2023

Abstract
Kawasaki disease (KD), the leading cause of acquired heart disease in children, primarily affects infants and toddlers. Future studies on KD immune responses are hampered by a limited understanding of normal immune responses in these ages. Plasmablasts are a transitional form of B cells that lead to long-term plasma cells, and their levels rise in the peripheral blood after exposure to a foreign antigen. In adults, these responses are both temporally and functionally well characterized. To date, there have been few studies on plasmablasts in the predominant age range of KD.
This study is focused on characterizing the normal plasmablast responses in the predominant age range of KD presentation. Children presenting to an urban pediatric emergency room who had fever and symptoms overlapping those of KD, were recruited. Peripheral blood mononuclear cells were isolated and evaluated utilizing flow cytometry with specific B cell markers from 18 KD subjects and 69 febrile controls.
Plasmablast numbers and timing of response are similar between infectious disease control and KD subjects. In both groups, infants have diminished plasmablast responses compared to older children. Using deep sequencing, immunoglobluin variable gene usage and sequences will be compared between infants and older children.
In this single-time point survey, we demonstrate that infants have a blunted peripheral plasmablast response. Overall, similar plasmablast responses in KD and controls support an infectious disease relationship to KD. Future time-course studies of plasmablasts in infants are warranted as this phenomenon may contribute to observed poor serum immune responses and maintenance of such responses in this age group.
Mitochondrial dynamics and metabolic programming in Th17 cell fate
Authors: Decker Carl William , Choi Clarice , Cave Si , Hernandez Jeniffer B. 
Published: January 2023

Abstract
Th17 cells have quickly become a paradigm of intense research interest, owing in part to their central role in mediating tissue-immune system communication, their demonstrable anti-tumor capacity, and their involvement in the pathogenesis of several autoimmune disorders. As with other effector Th1 and Th2 cells, they are members of a lineage derived from CD4 naïve cells, differentiating from their progenitors in response to immunological need. Recent research has revealed that differentiation of memory T-cells is dependent on the morphology of fluid mitochondrial networks, and in particular on remodeling dynamics that yield fused mitochondrial superstructures that favor oxidative phosphorylation-driven metabolism. In a similar fashion, our data suggest that Th17 T-cell differentiation is contingent upon highly fissed mitochondria network morphology, wherein a more independent arrangement of mitochondria and increased aerobic glycolsysis is employed. An important component of this research is the modulation of DRP-1, a GTPase that when phosphorylated in the cytosol initiates fission mitochondrial dynamics. Specifically, our data suggests that attenuation of DRP-1 action may play an important role in Th17 differentiation, and thus a better understanding of Th17 metabolism and how it affects immune cell fate, which at this time is poorly characterized.
Unilateral corneal nerve cutting induces bilateral dry eye disease in a murine model.
Authors: Kim Kyoung Woo , Lee Hyo Kyung , Ryu Jin Suk , Jeong Hyun Jeong , Yoon Chang Ho , Kim Mee Kum 
Published: January 2023

Abstract

Purpose
To investigate the effect of the severing of corneal basal nerve plexus in one eye on bilateral dry eye disease in a murine model.

Methods
6 week-old female BALB/c mice were divided into control (n=30) and nerve-cutting (NC) groups (n=30). The left cornea was partially incised with a 2.0mm circular trephine, through the upper two-thirds of the cornea stromal layer. Lissamine green corneal staining and tear volume measurements were performed every week for 4 weeks. At 2 and 4 weeks, dendritic cells, CD4+/CD8+ T cells, regulatory T cells in cervical lymph nodes, conjunctivocornea and spleens were analyzed by flow cytometry. With real-time RT-PCR, neuropeptides were also analyzed in intra-orbital lacrimal glands at 2 weeks.

Results
In bilateral eyes of mice in NC group, corneal staining grades were increased and tear volumes were decreased. CD11c+CD86hi, CD11c+MHCIIhi cells in conjunctivocornea were increased in trephined eyes at 2 weeks and in contralateral eyes at 4 weeks. CD69 were highly expressed in CD4+/CD8+ T cells in conjunctivocornea of trephined eyes at 4 weeks. CD8+IFNγ+ T cells were increased in contralateral cervical lymph nodes in NC group. Meanwhile, regulatory T cells in spleens were significantly suppressed in NC group. In addition, neuropeptide Y and neutrin were increased in intra-orbital lacrimal glands in NC group

Conclusions
It suggests that unilateral corneal nerve cutting may induce bilateral dry eye disease by entering activated dendritic cells into the bilateral eyes with a disturbance of immune privilege.
Intestinal epithelium intrinsic RARα signaling regulates gut barrier integrity via IL-18
Authors: Iyer Namrata R. , Vaishnava Shipra 
Published: January 2023

Abstract
Intestinal epithelium, overlying mucus layer and anti-microbial peptides together form a physico-chemical barrier crucial for homeostasis with the gut microbiota. Intestinal epithelial cells (IECs) are at the frontline of host-microbe interactions in the gut, yet how they modulate barrier function in response to dietary cues is poorly understood. Vitamin A and its key metabolite retinoic acid (RA), are crucial regulators of gut immune homeostasis. In this study, we employ a mouse model that expresses a dominant negative retinoic acid receptor exclusively in IECs (dnRARVillin-Cre) to establish a novel role for RA signaling in regulating the mucus barrier. The absence of RA signaling in colonic epithelium resulted in significant increase in mucus layer thickness indicating that RA regulates goblet cell function. Concomitant with this, we observed that in dnRARVillin-Cre mice there are more goblet cells and an enhanced spatial separation between host and the gut microbiota. Further, we showed that dnRARVillin-Cre mice have a diminished sensitivity to chemically induced colitis in comparison to wild-type mice. Quantitative RNA and protein analysis uncovered that gene transcription and protein activation and secretion of key pro-inflammatory cytokine IL-18 was severely impaired in epithelium of dnRARVillin-Cre mice. IL-18 has previously been shown to act as a negative regulator of goblet cell function in the intestinal epithelium. We now show that intestinal epithelium intrinsic RA signaling can modulate IL-18 levels to regulate the mucus barrier. Our results have thus disclosed a novel link between a diet derive metabolite and intestinal epithelial cell function that can be harnessed to modulate mucosal immunity.
The metabolic basis of resistance to Adoptive T Cell Therapy (ACT) in patients with solid tumors
Authors: Peng Weiyi , Cascone Tina , McKenzie Jodi , Mbofung Rina , Punt Simone , Wang Zhe , Xu Chunyu , Williams Leila , Wang Zhiqiang , Bristow Christopher , Carugo Alessandro , Peoples Michael , Li Lerong , Karpinets Tatiana , Huang Lu , Malu Shruti , Creasy Caitlin , Leahey Sara , Chen Jiong , Bernatchez Chantale , Gopal Vashisht , Heffernan Timothy , Hu Jianhua , Wang Jing , Amaria Rodabe , Wistuba Ignacio , Woodman Scott , Roszik Jason , Davis Eric , Davies Michael , Heymach John , Hwu Patrick 
Published: January 2023

Abstract
Adoptive T cell therapy (ACT) has produced impressive responses in a subset of patients with advanced malignancies. However, majority of patients still failed to respond. Thus, there is an urgent need to understand the resistant mechanisms in non-responders and develop more effective ACT strategies. Here, we employed two independent and unbiased approaches to identify novel molecular determinants of immune resistance. We generated gene expression profiles on an immune resistant melanoma cell line to identify alternative immunosuppressive mechanisms. In addition, we utilized a new high-throughput shRNA screening platform developed by our group to functionally interrogate immune resistance in patient-derived melanoma cells. Results from both analyses implicated tumor-associated glycolysis as a critical pathway that enables tumor cells to evade T cell-mediated antitumor activity. By using samples from melanoma and non-small cell lung cancer patients, we showed that increased expression of glycolysis-related genes is associated with poor T cell infiltration of tumors. Moreover, we found that increasing tumor glycolysis impaired T cell killing of melanoma cells, while inhibiting glycolysis restored T cell-mediated apoptosis of tumor cells. More importantly, from two non-overlapping ACT-treated patient cohorts, we discovered that tumor glycolytic activity in patients who experienced disease progression following ACT was significantly higher compared to those patients who were responsive to therapy. Taken together, our results demonstrate that tumor glycolytic metabolism is associated with the efficacy of ACT and identify glycolysis as a candidate target for combinatorial therapeutic intervention.
Effect of 3,3′-Diindolylmethane on Gut Microbiome in Colorectal Cancer
Authors: Alrafas Haider Rasheed Daham , Busbee Brandon , Nagarkatti Prakash , Nagarkatti Mitzi 
Published: January 2023

Abstract
Colorectal cancer (CRC) is the third most commonly diagnosed cancer in the world, and currently there is no cure for CRC. In the current study we investigated the effects of 3,3′-diindolylmethane (DIM) on the murine azoxymethane-dextran sodium sulfate (AOM-DSS) CRC model. Our data shows that administration of DIM alleviates symptoms associated with CRC. Endoscopy and histopathology showed DIM decreased colonic tissue damage and tumor growth. In addition, DIM was able to decrease myeloid-derived suppressor cells (MDSCs) in the blood and spleen in the AOM-DSS model. DIM treatment also significantly altered T cells populations which included decreases in Tregs and IL-10 producing T cells while increasing in Th1 and Th17 cells. We performed 16S rRNA sequencing of cecal flushes and validation with PCR revealed that AOM-DSS administration led to significant decreases in bacterial species Ruminococcus gnavus, Akkermansia muciniphila, Bifidobacterium pseudolongum, Haemophilus parainfluenza, and Acineobacter lwoffi, while increasing species such as Bacteroides acidifaciens, Bacteriodes ovalus, and Parabacteroides distasonis. However, mice that were treated with DIM showed a reversal in these gut microbial alterations caused by AOM-DSS CRC induction. We quantified short chain fatty acids (SCFA). AOM-DSS administration led to a significant decrease in i-butyric and n-butyric acids, however, mice that were treated with DIM increased these levels significantly. Finally we performed fecal transfer experiments to confirm that the alterations in gut microbiome by DIM mediated the anti-cancer effects. Collectively, these data show that DIM can ameliorate CRC by preventing cancer-associated gut microbial dysbiosis
Brain tumor-induced neuronal stress orchestrates adaptive immune surveillance through fractalkine
Authors: Nwajei Felix , Shanmugasundaram Meenakshi , Paine Dana , Zal Anna , Beceren-Braun Figen , Gabrisiewicz Konrad , Zhou Shouhao , Lee Sungho , Rodriguez Benjamin , Heimberger Amy , Zal Tomasz 
Published: January 2023

Abstract
Tissue damage contributes to initiation and modulation of an immune response. Tumor progression generally causes distress to the surrounding tissue. However, how tumor-induced parenchymal damage regulates anti-tumor immune response remains to be understood. We found that tumors that invaded brain parenchyma compressed the surrounding neurons causing increased expression of the neuronal chemokine CX3CL1/fractalkine in the peritumoral margin. Intravital two-photon microscopy revealed perivascular recruitment of monocyte-derived CD11c+ dendritic cells and T cells that interacted and killed individual cancer cells in tumor margins. Immune surveillance of brain tumors became inefficient in mice lacking the receptor for fractalkine, CX3CR1, resulting in more aggressive tumor progression. Our results identify tissue stress and associated chemokine signaling as a potential target to orchestrate anti-tumor immune surveillance in the brain.
Development of syngeneic NOD tumor models to study tumor immunity in autoimmune-prone mice.
Authors: Young Arabella , Nguyen Vinh , Mehdizadeh Sadaf , Sheehan Kathleen C. F. , Serreze David V. , Schreiber Robert D. , Bluestone Jeffrey A. 
Published: January 2023

Abstract
With increasing use of cancer immunotherapies, it is evident that some patients develop immunotoxicity, termed immune-related adverse events (irAEs). Many of these irAEs are a consequence of a peripheral breakdown in self-tolerance but the basis, be it genetic, epitope spreading or environment, remains unclear. This highlights an urgent need to develop preclinical models to profile autoimmunity together with anti-tumor immunity to accurately assess the etiology by which autoimmune pathologies are induced in immunotherapy-treated cancer patients. We generated transplantable syngeneic tumor cell lines in the autoimmune-prone NOD background from spontaneous tumors and methylcholanthrene (MCA)-induced fibrosarcomas. We investigated whether the presence of tumor altered the severity and frequency of autoimmunity in response to cancer immunotherapies. Anti-PD-1, but not anti-CTLA-4, accelerated the onset of autoimmune type 1 diabetes (T1D), similarly observed in a proportion of anti-PD1-treated cancer patients, while also providing improved tumor control and altering the expression of immunomodulatory markers (including CD73, CD39, PD-1) in both pancreatic islets and periphery. In addition, using NOD mice, congenic for the insulin-dependent diabetes (Idd) susceptibility gene Idd9, we determined that the NOR-derived gene locus provided significant protection from anti-PD-1-induced T1D. Tumor studies are underway in these and other Idd congenic NOD mice. Together, these preclinical models provide a platform to assess safety profiles for cancer immunotherapies, identifying cellular mechanisms and therapeutic interventions that inhibit the development of autoimmunity while preserving anti-tumor immunity.
Targeting inflammation to prevent breast cancer metastasis
Authors: Holl Eda K. , Frazier Victoria , Boczkowski David , Sullenger Bruce , Nair Smita K. 
Published: January 2023

Abstract
Biomarkers associated with systemic inflammation correlate with poor prognosis in cancer patients. Circulating cell-free DNA (cfDNA) is released passively and actively by both tumor cells and host cells and cfDNA levels in blood correlate with tumor burden in many tumor types. Notably, studies in breast cancer have shown that inhibition of cfDNA has a significant effect in reducing invasion and migration in vitro. We have previously demonstrated the ability of nucleic acid binding polymers (NABPs) to bind and inhibit the pro-inflammatory effects of cfDNA and RNA in models of systemic lupus erythematosus and influenza. Herein, we demonstrate that in tumor bearing mice, levels of cfDNA increase with tumor burden and decline post NABP in vivo administration. Using an orthotopic breast cancer murine model we demonstrate that NABP treatment, following surgical resection, results in reduced or completely absent lung metastasis. In addition, intravenous delivery of breast cancer cells in the presence of NABPs also results in decreased tumor cell lung seeding and lung metastasis. Taken together, our data suggest that NABPs can be used to target cfDNA and inhibit such DAMPs from activating pathological inflammation, an innovative approach to treat cancer progression and metastasis. In particular, NABPs may be useful in the clinical setting following standard of care surgical tumor resection.
Utilizing the 2017–2018 seasonal influenza vaccine as a treatment for cancer
Authors: Newman Jenna H. , Chesson Charles Brent , Aspromonte Salvatore , Bommareddy Praveen K. , Pepe Russell , Tarabichi Saeed , Li Shengguo , Jhawar Sachin , Herzog Nora L. , Aboelatta Mones , Kaul Eshan , Estupinian Ricardo , Kane Michael P. , Silk Ann , Zloza Andrew 
Published: January 2023

Abstract
In recent years, immunotherapy has yielded increased survival for cancer patients; however, a significant percentage of patient tumors remain refractory to immunotherapy. This is due in part to the absence of an inflamed tumor microenvironment. In our effort to utilize anti-pathogen vaccination to recruit immune cells to un-infiltrated (cold) tumors, we observed that intratumoral injection of influenza A/PR8/H1N1 lysate (but not live virus) reduced B16-F10 melanoma growth (p&lt;0.01). Towards determining whether FDA-approved human vaccines could likewise be utilized, we administered a quadrivalent 2017–2018 human seasonal influenza vaccine via intratumoral injection to mice, significantly slowing tumor growth relative to that of PBS-injected controls (p&lt;0.05). Analysis of RNA from tumor homogenates via the NanoString PanCancer Immune Profiling Panel indicated upregulation of transcripts for chemokines (CCL5, CXCL9), immune checkpoints (PD-L1, LAG3), and HLA molecules – hallmarks of an inflamed (hot) tumor phenotype. In addition to halting tumor growth, intratumoral administration of the human influenza vaccine protected mice from subsequent intranasal influenza challenge. Our findings suggest that intratumoral administration of human vaccines can reduce tumor growth, in part by converting “cold” tumors into “hot” (immune-infiltrated) tumors, while simultaneously providing protection against infection. Future studies will address the efficacy of vaccination in humanized mouse models and the possibility of synergy with checkpoint blockade therapies, in an effort to evaluate the potential of microbial-based therapies as a dual vehicle for cancer treatment and infection prevention.
HIV-1 and HIV-2 induce Interferon-lambda production by plasmacytoid Dendritic Cells
Authors: Hosmalin Anne , Isnard Stéphane , Vimeux Lene , Guillerme Jean-Baptiste , Ramirez Bertha Cecilia , Morel Marina , Cheynier Rémi , Iannetta Marco 
Published: January 2023

Abstract
Type III Interferons (IFN-λ) were barely studied during HIV infection, despite their antiviral properties similar to those of type I IFN and their important role during HCV infection, where IFN-λ3 gene polymorphisms correlate with viral clearance. We tested IFN-λ responses to HIV-1, and also to HIV-2, which is less pathogenic.
We first stimulated PBMC (EFS-Inserm convention) enriched for dendritic cells (DC), the main IFN producers. Purified HIV-1 virions or H9 T cells chronically infected with HIV-1 induced transcription of IFN-λ1 and 2/3 mRNA (RT-qPCR), as well as the secretion of IFN-λ (ELISA). Similar results were obtained with HIV-2-infected cells or virions. Intracellular labeling for IFN-λ1 was detected by flow cytometry in BDCA-4+ plasmacytoid DC (pDC), but not in BDCA-1+ or -3+ conventional DC (cDC). This was confirmed in &gt; 95% purified cell populations. Recognition of HIV-1 or HIV-2 by pDC induced their maturation (surface CD83 and CCR7 overexpression), and bystander maturation of cDC.
Therefore, IFN-λ production by human blood pDC was induced at comparable levels by HIV-1 or HIV-2, either as cell-free viruses or as infected cells, indicating that it is not a clue for the difference in host-pathogen relationship between the two viruses, and that IFN-λ may contribute to the Interferon-Stimulated-Gene response during HIV infection. Knowledge of IFN-λ responses to HIV will help modulating IFN responses toward viral control and against pathogenic immune hyperactivation.
EBV infection modulates the cell viability of gastric cancer cell through modulating miR34a-NOX2-ROS signaling
Authors: Hur Daeyoung , Yun Sun-mi , Choi Dabin , Kim Seon Hyun , Lee Mi Kyung , Kim Yeong Seok 
Published: January 2023

Abstract
Epstein-Barr virus (EBV) nuclear antigen 1 (EBNA1) is a viral protein expressed in all EBV-infected cells that induces malignant transformation. EBNA1 is reported to contribute to tumor progression through an increase in reactive oxygen species via nicotinamide adenine dinucleotide phosphate oxidase. However, the underlying molecular mechanism of EBNA1-induced ROS accumulation in gastric cancer is poorly understood. Here, we demonstrated that miR34a regulation by EBNA1 determined cell fate in EBV-infected gastric cancer cells. ROS content and NOX2 expression were higher in EBNA1-expressing SNU719 cells than in EBNA1-nonexpressing SNU638 cells. Downregulation of NOX2 using siRNA technology in SNU719 cells decreased cell viability and ROS content. Regulation of EBNA1 expression in EBV-associated gastric cancers modulated NOX2 expression, ROS content and cell viability. We also showed that upregulation of NOX2 by EBNA1 was mediated by downregulating miRNA34a. Finally, overexpression of miR34a in EBNA1-expressing SNU719 cells induced typical apoptosis, suggesting that reactivation of miR34a in EBNA1-expressing gastric cancer cells could be a strategy for treatment of EBV-infected gastric cancer cells.