bluuebunny/crossref_metadata_2025_split huggingface dataset:
Chronic immune barrier dysregulation among women with a history of violence victimization
Authors: Kohlmeier Alison , Haddad Lisa B , Li Tiger Zheng-Rong , Brookmeyer Kathryn A , Baker James M , Chen Cheng Y , Kersh Ellen N , Herbst-Kralovetz Melissa M. , Hogben Matthew , Ofotokun Igho , Kohlmeier Jacob E 
Published: January 2023

Abstract
We explored the association between violence victimization and increased risk for acquiring sexually transmitted infections (STI) in women by measuring cellular immune barrier properties from the female reproductive tract (FRT). STI-negative participants reporting repeated prior victimization occurrences through the lifetime trauma and victimization history (LTVH) instrument were more likely to exhibit alterations in barrier homeostasis and the composition of critical immune mediators irrespective of demographic parameters or presence of bacterial vaginosis. By combining cellular data with mixed-effect linear modeling, we uncovered differences in local T cells, MHCII+ antigen presenting cells, and epithelial cells indicative of altered trafficking behavior, increased immunosuppressive function, and decreased barrier integrity at sites of STI exposure that correlate with LTVH score. These data evidence a biological link between a history of violence victimization and risk of STI acquisition through immune dysregulation in the female reproductive tract.
Synergy between T-dependent antibodies and IL-10 limits susceptibility to inflammatory bowel disease
Authors: Landuyt Ashley E , Klocke Barbara J , Schoeb Trenton R , Maynard Craig L 
Published: January 2023

Abstract
Inflammatory bowel diseases (IBD) are chronic autoinflammatory conditions in which the immune system loses tolerance to gastrointestinal microbes. The role of humoral immunity in IBD is largely undefined. We examined the potential of T-dependent antibodies to prevent intestinal inflammation using mouse models of IBD. For this, we used mice without inducible T cell costimulator ligand (ICOSL). Icosl−/− mice produce significantly fewer T-dependent antibodies. When tested, we found Icosl−/− mice had similar IgA binding but significantly reduced IgG binding to mucosally-associated microbes. Additionally, Icosl−/− mice have more CD4 T cells producing IL-10, an immunosuppressive cytokine, in the colon. We hypothesized that T-dependent antibodies and IL-10 cooperatively promote intestinal homeostasis. To test this, we temporarily eliminated IL-10 producing cells from adult mice. Icosl−/−, but not wild type or IgA−/− mice, rapidly developed colitis under these conditions. This colitis could be prevented if mice were first depleted of Gram-positive or anaerobic bacterial flora. We further investigated the synergy between these T-dependent antibodies and IL-10 utilizing mice with a codeletion of CD4 T cell-derived IL-10 (Il10cKO) and ICOSL. This codeletion resulted in colitis before 28 days of age. However, fostering Icosl−/− Il10cKO mice on wild-type mothers delayed this early-onset inflammation. This suggests T-dependent antibodies conveyed through breastmilk are protective against early-onset colitis. Collectively, our results suggest that IL-10 and T-dependent antibodies toward mucosa-associated Gram-positive anaerobes continually cooperate to maintain intestinal homeostasis throughout the lifespan.
Deficiency in B Cell Maturation Antigen reveals gender differences in Experimental Autoimmune Encephalomyelitis
Authors: Kumar Gaurav , Ko Rose M , Axtell Robert C. 
Published: January 2023

Abstract
Multiple sclerosis (MS) is immune mediated demyelinating disease of the central nervous system (CNS) leading to neuronal damage. The disease is heterogeneous with respect to onset and clinical course, being more prevalent in women than in men with a ratio of 3:1. Further sex differences have been observed with males having a more severe and debilitating disease course compared to female. The complex interplay of immune cells, sex hormones or genetic differences could be contributing to these clinical phenomena, which remains to be elucidated. In experimental autoimmune encephalomyelitis (EAE), a mouse model of MS, several reports have demonstrated no sex differences in disease onset or severity in C57BL/6 mice. Herein we report that deficiency in B Cell Maturation Antigen (BCMA) in C57BL/6 mice reveals a sex difference in EAE. BCMA plays a prominent role in B cell function, however, the role BCMA plays in MS and EAE is unknown. Our initial goal of this project was to determine the impact BCMA deficiency has on EAE. In doing so we confirmed that EAE disease was not different in males and females from BCMA+/+mice. Strikingly in the BCMA−/− mice, there was a significant increase in EAE disease severity in the males compared to females. The increased EAE in the BCMA−/− male mice was associated with increased demyelination and infiltration of inflammatory T cells and macrophages into CNS. Also, we observed decreased splenic transitional B cells in male BCMA−/− mice compared to females. Altogether, our data demonstrate that male BCMA−/− have elevated inflammatory responses compared to females leading to increased neuro-inflammation. Further experiments are underway to define the specific mechanisms behind the sex differences in BCMA deficient mice.
GMCSF-neuroantigen vaccines engender FOXP3+ regulatory T cell responses through low-efficiency self-antigen recognition events integrated through diminished CD40L-CD40 signaling
Authors: Moorman Cody D , Mannie Mark D 
Published: January 2023

Abstract
Neuroantigen (NAg)-specific tolerogenic vaccines that induce myelin-specific FOXP3+ regulatory T cells (Tregs) may be an effective treatment for Multiple Sclerosis. Previous studies showed that fusion proteins comprised of GM-CSF and NAg (GMCSF-NAg) are potent tolerogens that inhibit several rodent models of experimental autoimmune encephalomyelitis. GMCSF-NAg-induced T cell responses were investigated in vivo by use of 2D2-FIG mice, which have a FOXP3 GFP reporter (FIG) and a transgenic TCR (2D2) which recognizes myelin oligodendrocyte glycoprotein peptide 35–55 (MOG) as a low-efficiency antigen and neurofilament medium peptide 13–37 (NFM) as a high-efficiency antigen. A single subcutaneous vaccination of 2D2-FIG mice with GMCSF-MOG resulted in high numbers and percentages of Tregs in the blood, spleen, and lymph nodes, whereas GMCSF-NFM elicited a dominant conventional T cell (Tcon) response. To determine how low and high-efficiency TCR responses regulate cell lineage fate, we investigated TCR-induced CD40L expression. GMCSF-NFM, but not GMCSF-MOG, induced significant CD40L expression when cultured with 2D2 responder T cells. Pretreatment of 2D2-FIG mice with an agonistic anti-CD40 monoclonal antibody prevented GMCSF-MOG induction of Tregs and favored Tcon responses. MOG35–55 was a partial TCR antagonist that blocked NFM stimulation of CD40L expression in 2D2 T cell cultures. Similarly, GMCSF-MOG was functionally dominant and induced Tregs in 2D2-FIG mice when mixed with an equimolar dose of GMCSF-NFM. These data indicated that low-efficiency antigen recognition is a key parameter for the induction of Treg responses and is in part controlled through CD40L-CD40 signaling pathways to determine T cell lineage fate.
Identification of markers of relapse in a relapsing-remitting mouse model of multiple sclerosis
Authors: Chase Carol Ann , Forsthuber Thomas 
Published: January 2023

Abstract
Approximately 85 percent of individuals newly diagnosed with multiple sclerosis have the relapsing-remitting form of the disease characterized by attacks of neurologic symptoms that are both unpredictable in occurrence and duration. The lack of markers that reliably predict the occurrence of multiple sclerosis relapses hinders the ability for proactive therapeutic intervention. To address the urgent need for biomarkers of relapse we investigated proteome changes over the disease course of relapsing-remitting experimental autoimmune encephalomyelitis (EAE) in SJL mice as a preclinical model of the disease using a high-throughput quantitative proteomic technique. In this study, we utilized this established proteomic technique as well as bioinformatics tools to prioritize key proteins that were expressed differentially at different stages of disease including remission and relapse. Principal component analysis of protein expression shows that the remission and relapse phases of disease cluster separately, indicating distinguishable variation between the two disease states. Importantly, statistical testing identified proteins with differential expression in the CNS at different stages of disease, several of which are CNS specific. We are seeking to detect corollary changes in these CNS-specific proteins in the serum, pointing to a minimally invasive means of monitoring disease progress and measuring drug efficacy. Our studies will provide proof-of-concept for identifying homologous human biomarkers to guide treatment in individual patients. Furthermore, our results may provide insights into mechanisms that contribute to disease pathology and offer additional therapeutic targets.
Gemcitabine promotes tumor cell-derived inflammatory responses leading to immunosuppression
Authors: Ding Chuanlin , Yan Jun 
Published: January 2023

Abstract
Some chemotherapeutic agents can selectively deplete MDSC in vivo. However, recent studies suggest that Gemcitabine (GEM) and 5-Fluorouracil (5-FU) treatment decrease the anticancer efficacy by activating the inflammasome pathway in MDSC. In addition, chemotherapy can modify the tumor microenvironment by induction of chronic inflammation. Therefore, regulations of MDSC by chemotherapy still remain elusive. Here, we explored the mechanisms by which multi-dose clinical regimen of GEM treatment induce an ongoing inflammation leading to the enhanced immunosuppressive activity of monocytic MDSC (M-MDSC). We found that repeated GEM treatment promoted the expansion and differentiation of immunosuppressive M-MDSC although tumor development was delayed in E0771 tumor-bearing mice. Accordingly, IFN-γ-producing CD4 and CD8 T cells were significantly decreased in the TME of GEM-treated mice. The conditioned medium of GEM-treated tumor cells (GEM-CM) promoted the differentiation of immunosuppressive mouse BM Ly6Chigh cells. Tumor-derived soluble factors, such as GM-CSF and soluble ICAM-1(sICAM-1), were up-regulated upon chemo-drug treatment. Blocking of GM-CSF or ICAM-1 with neutralizing Abs could partially reduce immunosuppression of Ly6Chigh cells induced by GEM-CM. Enhanced production of reactive oxygen species (ROS) and activation of NF-κB were observed in GEM-treated tumor cells. Treatment with the inhibitor of NF-κB signaling could abrogate GEM-induced hyperexpression of GM-CSF in E0771 cells. Together, our results define an undesired effect of GEM-induced ROS which leads to NF-κB activation, up-regulation of GM-CSF, and subsequent differentiation of immunosuppressive myeloid cells.
Tumor exosome mediated immune regulation in colorectal cancer
Authors: Subramanian Subbaya , Zhao Xianda , Yaun Ce 
Published: January 2023

Abstract
Colorectal cancer (CRC) remains the third most common cause of cancer-related deaths in the United States. Most (~85%) of CRC tumors are nonimmunogenic, i.e. they lack a significant number of tumor-infiltrating T cells, and are typically unresponsive to the current immune checkpoint inhibitor-based therapies. T cells isolated from nonimmunogenic, microsatellite stable (MSS) CRC have lower levels of CD28, which provides a costimulatory signal required for T-cell activation, trafficking, proliferation, differentiation, and cytotoxic activity. CRC tumors have elevated levels of miR-503 and its cluster member miR-424, both directly target CD28 in vitro. Our data also showed that these miRNAs are present in extracellular vesicles (EVs) secreted by CRC cells, which are taken up by T cells and affect its proliferation and function in the tumor microenvironment. Further, EVs with these immune suppressive miRNAs support tumor progression in CRC mouse models. Strikingly, in orthotopic models of CRC, mice preconditioned or treated with modified EVs (EVs lacking functional miR-503 and/or miR-424 (Δ503/424-EVs)) are protected against tumor formation and have a significantly reduced tumor burden, while mice receiving control EVs or PBS solution all form tumors. Our results provide preclinical evidence that treating CRC patients with modified EVs (lacking immunosuppressive miRNAs) will significantly improve antitumor immune response and reduce tumor burden. These results provide insights on how cancer cells modulate and suppress the immune response, provide novel targets, and form the basis for a new anti-cancer therapeutic strategy.
Butyrophilin 3A1 is a Dynamic T Cell Regulator in Ovarian Cancer
Authors: Payne Kyle K , Gonzalez Ricardo Chaurio , Sanz Jairo Perez , Galindo Carmen Maria Anadon , Biswas Subir , Mine Jessica A , Perales-Puchalt Alfredo , Tsiganov Evgenii , Costich Tara Lee , Harro Carly M , Marrs Aubrey K , Lajoie Jason , Li Kun-Po , Ophir Michael , Eskiocak Ugur , Schmidt Michael , Gabrilovich Dmitry I , Conejo-Garcia Jose R 
Published: January 2023

Abstract
Ovarian carcinoma microenvironmental T cells exert clinically relevant pressure against malignant progression; however current immunotherapies rarely induce ovarian cancer regression. Here we investigate CD277-containing butyrophilin 3A1 (BTN3A1), a poorly investigated immunoregulatory pathway driven by myeloid and tumor cells in ovarian tumor beds. We show that BTN3A1 is overexpressed in ovarian cancer and is associated with a significant survival disadvantage in these patients (n=200). Concomitantly, ectopic expression of BTN3A1 on APCs inhibits αβ T cell proliferation and Th1 cytokine production. Proteomic analyses and binding assays demonstrate that BTN3A1 interacts with the CD45 phosphatase and elements of the TCR. Consequently, TCR ligation in the presence of BTN3A1 inhibits the segregation of CD45 from the immune synapse and blunts downstream signaling by antagonizing the phosphorylation of CD3Zeta, Lck, and Zap70. We developed fully human αCD277 antibodies which rescue αβ T cell proliferation and Th1 cytokine responses, while driving the infiltration of T cells into tumor beds, delaying ovarian tumor progression in novel BTN3A1+ humanized mice and xenograft studies. Paradoxically, αCD277 antibodies promote the activation of γδ T cells by driving a conformational transformation of BTN3A1. Thus, co-transfer of γδ and Ag-specific αβ T cells in the presence of αCD277 antibodies synergize to further impair malignant progression in vivo. Overall, we show that BTN3A1 drives αβ T cell dysfunction in ovarian cancer, while αCD277 antibodies transform this molecule from immunosuppressive to immunostimulatory by rescuing αβ T cells and activating γδ T cells, thus dynamically unleashing T cell-driven antitumor immunity.
Human intrinsic immunity factor SLFN11 promotes cell death upon DNA damages through cleavage of distinct type II tRNAs and inhibition of proteins syntheses related to DNA damage responses and repairs
Authors: Li Manqing , Kao Elaine , Malone Dane , Gao Xia , Wang Jean Y. J. , David Michael 
Published: January 2023

Abstract
Previously we showed that as an intrinsic immunity factor, human SLFN11 inhibits HIV viral proteins syntheses by modulating tRNAs abundances and exploiting the biased codon usage of the virus. Transcriptome analysis in vast collection of cancer cell lines revealed that SLFN11 is the only gene whose expression significantly sensitizes tumor cells to DNA damaging agents (DDAs). We hereby report that SLFN11 preferentially inhibits translation of genes involved in DNA damage response and repair, including ATR and ATM, upon DDAs treatment based on their distinct codon usages without disrupting early DNA damage response signaling. Type II tRNAs, which include all serine and leucine tRNAs, are cleaved in a SLFN11-dependent manner in response to DDAs. Genes with high TTA (Leu) codon usage such as ATR display utmost susceptibility to translational suppression by SLFN11 due to the extreme low abundance of cognate tRNA-Leu-TAA. Specific attenuation of tRNA-Leu-TAA with antisense oligonucleotides (ASO) sufficed to ablate ATR protein expression and restore DDA sensitivity of SLFN11-deficient tumor cells. Our study uncovered a novel mechanism of DNA damage response regulation mediated by SLFN11-dependent tRNA cleavage and codon-specific translational inhibition. The immunomodulation of SLFN11 expression and activation can be a potent novel approach to overcome the wide-spreading resistance of tumor cells to chemo-/radio-therapies.
IFN-γ inhibit ALDHbr breast cancer cells in murine 4T1 tumor model
Authors: Shi Guilan , Zhuang Xiufen , Wu Yanhong , Heller Richard 
Published: January 2023

Abstract

Background
Due to the heterogeneity of breast cancer cells, cytotoxic treatments targeting proliferative cancer cells could not eradicate all cancer cells. Compelling evidence suggests that breast cancer stem cells (BCSCs) have a crucial impact in current shortcomings of cancer therapy because they are largely responsible for tumor initiation, relapse, metastasis, and chemo-resistance. Cytokines in the tumor microenvironment can regulate the self-renewal and survival of BCSCs in a variety of ways.

Methods and Results
We have utilized in vitro and mouse xenograft models (immunocompetent Balb/c mice and thymus-deficient nude mice (Balb/c nude)) to examine the interaction between breast cancer stem cells (BCSCs) and T cells or cytokine IFN-γ. In vitro assay, such as migration and invasion and sphere-forming, we demonstrate that CD8+ T lymphocytes regulate aldehyde dehydrogenase (ALDH) expressing in BCSCs (ALDHbr 4T1 cells) may through cytokine IFN-γ. Utilizing immunocytochemistry, western blotting and gene expression microarray of ALDHbr vs ALDHdim 4T1 cells, we identified cytokine IFN-γ decreased ALDH1A protein expression and regulated the cancer stem cell population. In various in vivo-like screening assays, depletion of either CD4+ or CD8+ T cells associated with increased proportions of BCSCs.

Conclusion
The collective results suggest that IFN-γ as a highly secreted cytokine may affect cancer stem cells in mouse breast cancer model.
Complete workflows allow comprehensive tumor microenvironment analysis and culture of cell subsets of limited tumor patient samples
Authors: Evaristo Cesar , Siemer Ramona , Criado-Moronati Elvira , Baranska Anna , Gert Philipp , Agorku David , Hardt Olaf , Vorholt Daniela , Singh Aparajita , Dose Christian , Heemskerk Bianca , Richter Anne 
Published: January 2023

Abstract
Immunotherapy has proven clinical efficacy and tremendous potential. But clinical benefit is experienced by only a subset of patients, such that additional research is necessary to improve outcomes. In particular, analyze steady-state anti-tumor immunity and monitor the effects of therapy on the tumor microenvironement. However, TIL numbers can be very low. Flow cytometry phenotyping different cell populations requires dividing limited tumor material into multiple samples, reducing the number of cells available for analysis. Therefore, innovative tools and workflows are needed to maximize the quality of data obtained from limited tumor patient samples.
We established workflows combining tissue storage, dissociation, cell isolation and analysis. We developed new reagents for magnetic cell sorting, incorporating novel technology enabling the removal of magnetic beads and antibody fragments (REAlease®). Tumor-infiltrating (TI) T-, B-, Myeloid cells, cancer-associated fibroblasts and tumor cells were sequentially isolated and characterized by flow cytometry, multi-parameter imaging and transcriptomics. Importantly, purification of TI T cells with high viability was essential for high-resolution immune profiling by single cell transcriptomics.
In conclusion, we optimized workflows for the comprehensive analysis of the tumor microenvironement. Sequential isolation of the different cell types maximized the number of cells available for analysis. These workflows reduce experimental time and allow the performance of more complex experimental setups. We believe the use of these innovative tools and workflows can significantly increase the quality of the data obtained in immunooncology and immunotherapy research.
Combination of anti-CD40 and anti-PD1 revert M2 polarization to limit tumor growth in a genetically engineered blander cancer mouse model
Authors: Verdeil Gregory , Leblond Marine , Imbratta Claire , Speiser Daniel E 
Published: January 2023

Abstract
Bladder cancer (BCa) represents the fourth most common cancer in men with a poor patient prognosis for advanced disease. About 75% of patients present non-muscle invasive BCa (NMIBC) and 25% present muscle invasive BCa (MIBC) or metastatic disease. Although BCG immunotherapy is a common treatment of BCa, the dynamics of immune cell infiltration and its relevance for disease outcome are still not well understood. We took advantage of a genetic based mouse model of MIBC to obtain a profound understanding of the immune contexture over tumor development. P53Fl/Fl/PTENFl/Fl mice were injected with Cre recombinase-expressing adenoviral vectors directly into bladder by micro-surgery. We observed the presence of NMIBC, MIBC and the development of metastases at 5, 9 and 13 weeks after vector injection, respectively. As tumor evolves, we observed a transition from an anti-tumoral microenvironment (MHCIIhigh TAM, CD4 and CD8 TILs) to a pro-tumoral one (MHCIIlow TAM and MDSC), going along with an increased expression of PD-1 by T cells and accumulation of regulatory T cells. After testing various immunotherapy tretaments on mice with MIBC, we found out that combination of αCD40+αPD1 increases CD8 TILs infiltration and IFNg production, re-polarized TAM toward a M1-like phenotype and increased the survival of the mice.
Therapeutic targeting of the immunosuppressive axis in ovarian cancer using dietary supplements
Authors: Bollino Dominique , Webb Tonya J 
Published: January 2023

Abstract
Ovarian cancer is the deadliest gynecologic malignancy worldwide and mortality rates have remained steady despite advances in treatment. A major obstacle for current therapies is overcoming tumor immunosuppression, therefore targeting inhibitory factors produced in the tumor microenvironment could enhance antitumor responses. Natural Killer T (NKT) cells, a subset of T cells that recognize glycolipid antigens presented by CD1d, are important mediators of antitumor immune responses. We have previously shown that ovarian cancers shed the ganglioside GD3, which binds with high affinity to CD1d, thereby suppressing NKT cell activation. In addition to GD3, we have identified vascular endothelial growth factor (VEGF) as another immunosuppressive factor secreted by ovarian cancers. We found that VEGF inhibition results in decreased GD3 expression in human ovarian cancer cell lines and restoration of NKT cell responses. In addition, we found that treatment with VEGF can directly impair NKT cell functional responses. To therapeutically target the VEGF-GD3 signaling cascade, mouse and human ovarian cancer cell lines were treated with triptolide, a phytochemical which has demonstrated potent antitumor activity in vitro and in vivo. Treatment with triptolide reduces VEGF secretion by ovarian cancer cell lines and results in a concomitant decrease in the expression of GD3 synthase. In addition, pre-treatment of ovarian cancer cells with triptolide improves the ability of NKT cells to recognize and lyse the cancer cells. Thus, we have identified a novel therapeutic strategy that can be used to block the production of immunosuppressive factors, thereby restoring NKT cell-mediated antitumor immune responses in ovarian cancer.