bluuebunny/crossref_metadata_2025_split huggingface dataset:
Suppressing type I interferon enhances both autoimmunity and anti-tumor immunotherapy
Authors: Riding Rebecca L. , Fukuda Keitaro , Richmond Jillian M , Harris John E 
Published: January 2023

Abstract
Vitiligo is an autoimmune disease of the skin in which melanocytes are targeted for destruction by autoreactive CD8 T cells specific for melanocyte/melanoma-shared antigens, such as premelanosome protein (PMEL). We developed a mouse model of vitiligo through adoptive cell transfer (ACT) using PMEL-specific TCR transgenic CD8+ T cells (PMELs) and found that vitiligo pathogenesis is primarily driven by IFNγ. There is much crosstalk between IFNγR signaling and type I interferon signaling as type I interferons, including interferon α and β proteins, can directly regulate shared IFNγ target genes. Therefore, we sought to understand the role of type I interferons in vitiligo. We discovered that type I interferon α-receptor deficient (IFNAR−/−) host mice develop accelerated and more severe vitiligo compared to WT mice. Subsequent studies showed that IFNAR expression was not required on PMELs or the majority of other immune cells to suppress vitiligo, but rather on radioresistant cells. To determine whether this observation could be useful in melanoma immunotherapy, we tested ACT of PMELs in B16F10 melanoma-inoculated IFNAR−/− and WT mice and found that IFNAR−/− mice were relatively protected from the tumor, with a lower tumor burden and an elevated number of tumor-infiltrating PMELs compared to WT mice. Collectively, these results strongly suggest that type I interferon signaling suppresses anti-melanocyte immune responses in both autoimmunity and tumor immunity. We are currently investigating the mechanism of type I interferon suppression, specifically what cell types are driving this response and what mediators are involved.
Squamous cell carcinomas escape immune surveillance via inducing co-expression of PD-1 and LAG-3 inhibitory receptors on tumor infiltrating T lymphocytes
Authors: Wang Jing H , Mishra Ameet K , Kadoishi Tanya , Wang Xiaoguang , Driver Emily , Chen Zhangguo , Wang Xiaojing 
Published: January 2023

Abstract
Squamous cell carcinoma (SCC) is the second commonest type of skin cancer. About 90% of head and neck cancers are SCCs. It remains largely unknown how SCCs evade immune recognition. We recently established a mouse model by injecting tumor cells derived from primary SCCs harboring KrasG12D mutation and Smad4 deletion into wild-type (wt) or CD8−/− recipients. We found comparable tumor growth between wt and CD8−/− recipients, indicating a complete escape of CD8+ T cell-mediated anti-tumor responses by these SCCs. Mechanistically, CD8+ T cells were not defective in infiltrating tumors given their relatively increased percentage among tumor infiltrating lymphocytes (TILs). CD8+ TILs exhibited phenotypes of chronic activation and exhaustion, manifested with co-expression of programmed death 1 (PD-1) and lymphocyte activation gene-3 (LAG-3). Among CD4+ TILs, T regulatory cells (Tregs) were preferentially expanded. Contradictory to prior findings in melanoma, Treg expansion was independent of CD8+ T cells in our SCC model. Unexpectedly, CD8+ T cells were required for promoting NK cell infiltration within SCCs. Furthermore, we uncovered AKT-dependent lymphocyte-induced PD-L1 upregulation on SCCs, which was contributed greatly by combinatorial effects of CD8+ T and NK cells. Lastly, dual blockade of PD-1 and LAG-3 inhibited the tumor growth of SCCs. Thus, our findings identify novel immune evasion mechanisms of SCCs and suggest that immunosuppressive mechanisms operate in a cancer-type specific and context-dependent manner.
Targeted calcium influx boosts cytotoxic T lymphocyte function in the tumor microenvironment
Authors: Kim Kyun Do , Bae Seyeon , Capece Tara , Nedelkovska Hristina , de Rubio Rafael G , Smrcka Alan V , Jung Woojin , Park Byeonghak , Kim Tae-il , Srikanth Sonal , Gwack Yousang , Kim Minsoo 
Published: January 2023

Abstract
Adoptive cell transfer utilizing tumor-targeting cytotoxic T lymphocytes (CTLs) is one of the most effective immunotherapies against hematological malignancies, but significant clinical success has not yet been achieved in solid tumors due in part to the strong immunosuppressive tumor microenvironment. Systemic or intratumoral delivery of an immune boosting molecule to overcome local suppression has been proposed, but the full potential is limited by non-specific stimulation of tumor growth, metastasis, and angiogenesis. Here, we show that suppression of CTL killing by CD4+CD25+Foxp3+ regulatory T cell (Treg) is mainly mediated by TGFβ-induced inhibition of inositol trisphosphate (IP3) production, leading to a decrease in T cell receptor (TCR)-dependent intracellular Ca2+ response. Both in vitro and in vivo assays revealed that highly selective optical control of Ca2+ signaling in adoptively transferred CTLs was sufficient to overcome immunosuppression at the tumor site by enhancing T cell activation, IFN-γ production and antitumor cytotoxicity, leading to a significant reduction in tumor growth in mice. Together, our findings indicate that the targeted optogenetic stimulation of intracellular Ca2+ signal allows for the remote control of cytotoxic effector functions of adoptively transferred T cells with outstanding spatial resolution by boosting T cell immune responses only at the targeted tumor sites.
ID2-dependent anti-tumor immunity promotes anti-cancer therapies effects
Authors: Guo Xiaohuan 
Published: January 2023

Abstract
More and more studies show that the efficacy of many kinds of anti-cancer therapies, including chemotherapy, radiotherapy, targeting therapy and even immunotherapy, require host activated anti-tumor immune responses. However, the regulation mechanisms of anti-tumor immunity are not fully understood yet. Here, we show that a transcription regulator, Inhibitor of DNA binding 2 (ID2), could positively regulate the anti-tumor immunity. E and ID proteins are both HLH proteins and play important roles in the development of various immune cells. E proteins can form homodimers or heterodimers with HLH proteins and function as transcription activators or repressors, while ID proteins can prevent E proteins from binding to DNA. With a T cell specific ID2 knockout mice (Cd4-cre; Id2 fl/fl), we found that the anti-cancer efficacy of oxaliplatin and anti-PD-L1 treatment for subcutaneous transplant tumor model required ID2 expression in T cells. Further experiments showed that these anti-cancer therapies could induce IFNg production in wild type mice, but failed in ID2 deficient mice. Moreover, the tumor infiltrating cytotoxic CD8+ T cells, but not CD4+ T cells, were dramatically reduced in ID2 deficient mice compared their littermate controls. Our hypothesis is that post the anti-cancer therapy, ID2 could be upregulated and promote CD8+ T cell activation and migration into the tumor sites, then mediate the anti-tumor effect. Since E proteins are main targets of ID2, small molecules targeting E protein may be new choices for boosting anti-tumor immunity to enhance the efficacy of anti-cancer therapies.
Supported by grants from Tsinghua University and The Recruitment Program for Young Professionals (to X.G.).
Prevention and reversal of adverse humoral immune response by BAR-transduced regulatory T cells
Authors: Zhang Ai-Hong , Yoon Jeongheon , Kim Yong Chan , Wang Hong , Scott David W. 
Published: January 2023

Abstract
Antigen-specific elimination of unwanted immune response, such as anti-FVIII neutralizing antibody formation in hemophilia A patients, is highly desirable but remains a challenge. Analogous to the chimeric antigen receptor (CAR) strategy successfully used in cancer immunotherapy, we have created a chimeric receptor comprising a protein antigen or its domain, linked with the transmembrane and signal transduction domains, CD28-CD3ζ. We termed it “BAR” for B-cell-targeting antibody receptor. CD4+CD25hiCD127low human Tregs were retrovirally transduced to express a BAR containing the immunodominant FVIII C2 (C2 BAR) or A2 domain (A2 BAR). Control human Tregs were transduced to express a BAR containing chicken ovalbumin (OVA BAR). FACS sorted, BAR transduced human CD4+ Tregs have been successfully expanded in vitro, and shown to maintain phenotypic Treg markers in terms of co-expression of Foxp3 and Helios. Pretreatment of naïve hemophilia A mice with a mixture of C2 BAR plus A2 BAR human Tregs completely prevented anti-FVIII antibody development in response to FVIII/IFA immunization for as long as 8 weeks. More importantly, BAR human Tregs also effectively suppressed anti-FVIII antibody formation in primed animals with detectible pre-existing anti-FVIII antibodies. Further mechanistic studies suggest that the FVIII-specific B cell response were directly suppressed while the T cell response remained intact. Taking together, we report here a successful proof of principle strategy utilizing FVIII-specific BAR Tregs to directly target FVIII-specific B cells, an approach which could be adapted to address other adverse immune responses as well.
Macrophages play a pathogenic role in IL-23 mediated psoriasiform skin inflammation
Authors: Wang Yibing , Edelmayer Rebecca , Wetter Joe , Salte Katherine , Gauvin Donna , Leys Laura , Lippert Stephanie , Su Zhi , Miller Loan , Huang Susan , Honore Prisca , Kort Mike , McGaraughty Steve , Scott Victoria , Gauld Stephen B 
Published: January 2023

Abstract
Psoriasis (Ps) is an immune-mediated inflammatory skin disease that affects millions worldwide. Studying immune cells involved in Ps pathogenesis is essential to identify effective and safe therapeutics for the disease. Recent studies have demonstrated the involvement of macrophages in human Ps skin. Using an IL-23 murine model of psoriasiform dermatitis, which closely models human Ps, we have characterized the cellular lineage during disease progression and found continuous infiltration of macrophage as dominant immune population. Depletion of macrophages in the IL-23 murine model significantly reduced the inflammation as well as inflammatory mediators, such as TNFa, in the skin. This strongly suggests a pathogenic role of macrophages in the psoriasiform skin inflammation. Further characterization of this model revealed a number of phenotypically distinct macrophage populations suggesting they may play different roles in disease progression. Collectively, our data suggests that targeting macrophages may have therapeutic benefit for Ps patients.
Novel immunomodulatory proteins generated via directed evolution of variant IgSF domains
Authors: Evans Lawrence S , Levin Steven D , Rickel Erika , Wolfson Martin F , Dillon Stacey R , Kornacker Michael G , Swanson Ryan , Peng Stanford L 
Published: January 2023

Abstract
The immunoglobulin superfamily (IgSF) is a large, diverse family of proteins expressed on immune cells that have been extensively targeted for treatment of cancers and autoimmune diseases. Most of the therapeutic strategies targeting this family have focused on high affinity antibodies that bind a single receptor. Moreover, wild-type IgSF receptors typically exhibit low affinities for their counter-structures, limiting their utility in therapeutic modulation of immune responses. We have developed a novel variant Ig domain (vIgD™) platform using directed evolution and yeast display to affinity mature human IgSF extracellular domains. In this platform, libraries of mutagenized IgSF domains were selected for enhanced or altered affinity to specific recombinant proteins. Fc fusion proteins incorporating these evolved immunomodulatory IgSF domains were then tested in vitro for their ability to either agonize or antagonize T cell responses. Multiple novel vIgD™ fusion proteins have been generated that significantly attenuate T cell activation in vitro as assessed by proliferation and cytokine production. Lead molecules also exhibited in vivo efficacy in the human PBMC-NSG™ GVHD mouse model. Efficacy in vitro and in vivo was superior to wild-type IgSF domains due to the induced alterations in affinity for cognate ligand and through specifically directed changes in their ability to bind additional counter-structures. Our results demonstrate that vIgDs™ can be developed to acquire unique biochemical properties that significantly enhance therapeutic utility as immunomodulatory agents. This vIgD™ therapeutic platform has broad potential to enhance the activity of biologics in treatment of both autoimmune disease and cancer.
Therapeutic effect of Lactobacillus reuteri DSM 17938 on Treg-deficiency-induced autoimmunity (IPEX syndrome) via the inosine-adenosine 2A receptors
Authors: Liu Yuying , He Baokun , Hoang Thomas K. , Wang Ting , Taylor Christopher M. , Tian Xiangjun , Luo Meng , Tran Dat Q , Zhou Jain , Tatevian Nina , Luo Fayong , Molina Jose G. , Blackburn Michael R. , Gomez Thomas H. , Roos Stefan , Rhoads J Marc 
Published: January 2023

Abstract
Regulatory T-cell (Treg) deficiency causes lethal, CD4+T cell-driven autoimmune diseases. Stem cell transplantation is used to treat these diseases, but this procedure is limited by the availability of a suitable donor. The intestinal microbiota drives host immune homeostasis by regulating the development of Treg, Th1 and Th2 cells. It is currently unclear if Treg-deficiency autoimmune disorders can be treated by targeting the enteric microbiota. Our aims are to determine the autoimmunity, gut microbiota, and plasma metabolomics affected by probiotic Lactobacillus reuteri DSM 17938 (LR), and to further identify the mechanism of modulated metabolite(s) in suppressing autoimmunity in Treg-deficient scurfy (SF) mice. We demonstrated that Foxp3+Treg deficiency results in gut microbial dysbiosis and autoimmunity over the lifespan of SF mouse. Remodeling microbiota with LR prolonged survival and reduced multi-organ inflammation in SF mice. LR changed the metabolomics profile disrupted by Treg-deficiency with a major effect of restoring levels of the purine metabolite inosine. Feeding inosine itself prolonged life and inhibited multi-organ inflammation by reducing Th1/Th2 cells and their associated cytokines. Mechanistically, the inhibition of inosine on the differentiation of Th1 and Th2 cells in vitro depended on adenosine A2A receptors. Both A2A receptor specific antagonist or genetically knockout A2A to SF mice reversed the anti-inflammatory effects of both inosine and LR in vivo. In conclusions, A2A receptors mediate a substantial protective effect of inosine and LR. The LR-modulated-microbiota-inosine-A2A axis might represent a potential avenue for combatting autoimmune diseases mediated by Treg dysfunction.
MicroRNA-21a-5p/PDCD4 axis Regulates Mesenchymal-Stem-Cell-Induced Neuroprotection in Acute Glaucoma
Authors: Wang Julie , Su Wenru , Zheng Song Guo 
Published: January 2023

Abstract
The clinical application of mesenchymal stem cells (MSCs) yields promising therapeutic benefits for a variety of neurological diseases, but underlying mechanisms are poorly understood. Here we show that intravitreal infusion of MSCs promotes retinal ganglion cell (RGC) survival in a mouse model of acute glaucoma, with significantly decreased microglial activation, decreased production of TNF-α, IL-1β, and reactive oxygen species, and reduced caspase-8 and caspase-3 activation. In vitro, MSCs inhibit both caspase-8-mediated RGC apoptosis and microglial activation in part through stanniocalcin 1 (STC1). Furthermore, we found that microRNA-21a-5p (miR-21) and its target, PDCD4, are essential for STC1 production and neuroprotective properties of MSCs in vitro and in vivo. Importantly, our results also demonstrate that miR-21 overexpression or PDCD4 knockdown enhances MSC-induced neuroprotective effects in an acute glaucoma model. These data therefore uncover a previously unrecognized neuroprotective mechanism, by which the miR-21/PDCD4 axis induces MSCs to secrete STC1 and other factors exerting neuroprotective effects. Furthermore, the miR-21/PDCD4 axis is a promising new target for neuroprotection in IOP-induced retinal damage.
Synergistic enhancement of ISG54/ISRE promoter activity with combinations of Pattern Recognition Receptor agonists and Interferon-gamma
Authors: Guinn Zachary P , Brown Deborah M , Petro Thomas M 
Published: January 2023

Abstract
Induction of interferon stimulated genes (ISG)-54, which depends on activation of Interferon Regulatory Factor 3 (IRF-3), is critical for innate immune responses of virus-infected cells by reducing cell viability through the intrinsic apoptosis pathway. Using wild type (WT) and IRF3 deficient (IRF3KO) RAW 264.7 cell lines, genetically engineered to express secreted Lucia luciferase under control of an ISG54/ISRE promoter (RAW-Lucia), we saw that ISG54 promoter activity is IRF3 dependent in response to IFN-γ. To investigate IRF3 in responses to IFN-γ, WT and IRF3KO RAW-Lucia cells were stimulated with IFN-γ in the presence or absence of the IRF-3 agonist, Polyinosinic-Polycytidylic acid (PolyI:C). IFN-γ and PolyI:C synergistically enhanced ISG54/ISRE promoter activity in both WT and IRF3KO RAW-Lucia cells, however, this activity was 91% lower in IRF3KO compared to WT cells. Moreover, ISG54 promoter activity was negatively correlated with viability of WT RAW-Lucia. RAW-Lucia cells also responded in a similar fashion when stimulated with IFN-γ plus transfected PolyI:C or dA:dT, which are RIG-I/MDA-5 and STING agonists, respectively. Co-stimulation with IFN-γ and TLR7 agonist, Loxoribine-which activates IRF7 but not IRF3-also synergistically enhanced ISG54/ISRE promoter activity in WT and IRF3KO RAW-Lucia cells, but IRF3 deficiency reduced the synergistic enhancement of ISG54/ISRE promoter activity by 92%. In contrast, the TLR9 agonists, ODN1585, which also activates IRF7 but not IRF3, failed to stimulate ISG54/ISRE promoter activity in RAW-Lucia cells and only enhanced the response to IFN-γ by 30%. These studies further reveal a previously unnoticed IFN-γ/IRF3/ISG54 nexus that can be exploited for antiviral therapy.
Trehalose-6, 6′-dibehenate inhibits lipopolysaccharide-induced NF-κB activation via PLC-γ1-PKC-ERK signaling and promotes M2 microglial polarization
Authors: Lin Wan-Wan 
Published: January 2023

Abstract
Activation of microglia triggers a robust amount of pro-inflammatory cytokines, which are involved in the pathogenesis of central nervous system tuberculosis (CNS-TB). The mycobacterial cord factor (Trehalose-6, 6-dimycolate [TDM]), and its synthetic analogue Trehalose-6, 6-dibehenate (TDB) bind to C-type lectin receptors Mincle to activate macrophages and dendritic cells via the Syk/Card9 pathway. However, there are no studies have been conducted to determine the effect of TDB on inflammatory responses in microglia and its underlying signalling pathways. Here using BV2 microglial cells we found that TDB can inhibit NO production, iNOS, pro-IL-1β, and the pro-inflammatory gene expression of TNF-a, pro-IL-1β, IL-6, Mincle, IFNb and MIP2 in LPS-stimulated BV-2 microglial cells. TDB-induced ERK-1/2 activation in LPS-activated microglial cells, whereas TDB had no effect on p38 and JNK phosphorylation induced by LPS. Interestingly, TDB suppressed LPS-induced NF-κB nuclear translocation but did not affect the IKK activity, and these actions were reversed by ERK inhibitor. In addition, TDB caused PLC-γ1 and PKC activation in BV-2 cells, and the TDB-mediated ERK upregulation could be attenuated by PLC-γ1 and PKC inhibitors. TDB also induced AMPK activation via calcium/CaMKK dependent pathway. Moreover, TDB induced M2 gene expression in LPS-stimulated BV-2 cells, and this action was prevented by the AMPK inhibitor, indicating that AMPK activation participates in TDB-mediated M2 polarisation effects. Therefore, TDB may have therapeutic potential for mitigating microglia-mediated neuroinflammation.
Critical Role for NLRC3 in Cell Proliferation and Cancer
Authors: Karki Rajendra , Kanneganti Thirumala-Devi 
Published: January 2023

Abstract
The nucleotide-binding oligomerization domain-like receptors (NOD-like receptors, NLRs) are intracellular innate immune sensors of pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs), and are critical in regulating diverse range of biological functions. Genetic mutations in these cytosolic receptors are associated with chronic inflammatory or autoimmune disorders. NLRs are known to modulate inflammatory responses, cell death, proliferation, and/or the gut microbiota to attenuate tumorigenesis. We identified NLRC3, a poorly defined member of the NLR family, as a negative regulator of PI3K-mTOR signaling, and characterized the potential tumor suppressor function of NLRC3 in colorectal cancer. We showed that NLRC3 is critical in restricting tumorigenesis in both colitis-associated colorectal cancer (CAC) model and spontaneous mice model ApcMin/+. Mice lacking NLRC3 were hyper-susceptible to colitis and colitis-associated cancer (CAC). Likewise, ApcMin/+ mice lacking NLRC3 developed more tumors in the colon than that of ApcMin/+ mice. We further showed that NLRC3 pre-dominantly functions in intestinal epithelial cells. Mechanistically, enterocytes lacking NLRC3 were unable to control cellular proliferation owing to a failure to suppress activation of the PI3K-mTOR signaling pathways.
Polyamine blockade alters the neuroblastoma microenvironment to favor restriction of tumor growth
Authors: Bassiri Hamid , Vu Annette , Hogarty Michael D , Benavides Adriana D 
Published: January 2023

Abstract
Despite improved treatments, neuroblastoma (NB) still accounts for ~15% of childhood cancer deaths. Amplification of MYCN results in NB with high-risk features and poor 5yr survival. Interestingly, MYCN-amplified NBs have elevated polyamine (PA) levels, as the gate-keeper enzyme in PA synthesis, ornithine decarboxylase (ODC1), is a direct Myc target. Inhibition of ODC1 activity by the FDA-approved medication difluoromethylornithine (DFMO) results in modest growth reduction of NB cell lines in vitro, whereas DFMO administration to mice that are predisposed to developing MYCN-driven NBs (TH-MYCN+/+ mice) leads to survival extensions that were more profound than that predicted by the tumor-intrinsic activity of the drug alone. These observations implied that DFMO might also exert tumor-extrinsic effects on the tumor microenvironment (TME). Indeed, DFMO treatment of TH-MYCN+/+ mice alters the NB TME in several ways, the most profound of which is an increase in NK cell frequency. We also find an increase in the percentage of NB cells expressing NKG2D ligands, and alterations in the expression of NK cell stimulatory and inhibitory receptors to favor activation. Collectively, these findings suggest that PA blockade induces distinct TME changes that allow for more efficient immune control of NB growth. We are now testing whether the activity of DFMO is dependent on NK cells, and are delineating how DFMO alters the transcriptional profiles of NBs and immune cells in the TME. We hope that these studies will complement the data from phase I/II clinical studies using DFMO in various therapeutic strategies for NB, and will allow for an increased understanding of how to more effectively combine PA blockade with other immunotherapies for this disease.