bluuebunny/crossref_metadata_2025_split huggingface dataset:
Development of citrullinated-vimentin-specific CAR for targeting Tregs to treat autoimmune rheumatoid arthritis.
Authors: Raffin Caroline , Zhou Yu , Piccoli Luca , Lanzavecchia Antonio , Sadelain Michel , Bluestone Jeffrey A 
Published: January 2023

Abstract
Rheumatoid arthritis (RA) is one of the most common chronic autoimmune diseases with a frequency of 0.5–1.0% in the adult population of developed countries. RA is characterized by an aberrant inflammation of the synovial membrane that causes irreversible joint and bone damages. It has been previously described that regulatory T cells (Tregs) were defective in RA patients and that whereas Treg depletion increased the severity of the disease, Treg transfer efficiently reversed this effect in the collagen-induced arthritis (CIA) model, an animal model of RA. These studies strongly suggest that Treg therapy may be able to treat RA patients by inducing a long-term restoration of appropriate tolerance. Moreover, adding Ag-specificity to the expanded Tregs may promote their migration to the site of the abnormal inflammation and enhance their function. The aim of our study has been to engineer and expand chimeric antigen receptor (CAR)-expressing Tregs specifically targeting an antigen present in the joint of RA patients to induce a localized and effective immunosuppressive response. We developed a CAR directed against citrullinated vimentin (CV), a posttranslational modified intermediate filament protein known to be exclusively located in the extracellular matrix of the synovial tissue in 50% of the RA patients. We are currently working on transducing the CV-specific CAR into Tregs to then study the functional activity of these cells in vitro. We are also developing an in vivo protocol to assess the therapeutic efficacy of the CAR Treg transfer in CIA model. In conclusion, our project aiming to combine Treg therapy and CAR technology may lead to the development on a promising therapeutic tool to cure RA and potentially other autoimmune disorders.
Adenosine 2A Receptor Promotes Tolerance by Reducing Germinal Center Follicular Helper T cells and Pathogenic Class-Switched B cells
Authors: Schmiel Shirdi E , Yang Jessica , Kalekar Lokeshchandra , Jenkins Marc K , Mueller Daniel L 
Published: January 2023

Abstract
Enhanced production of high affinity class-switched autoantibodies contributes to pathological symptoms of autoimmune diseases. Full penetrance of autoantibody production appears to rely on help from germinal center follicular helper T cells (GC TFH cells). GC TFH cells promote the survival, differentiation, isotype class switch, and affinity maturation of B cells. Previous studies have reported that activation of Adenosine receptor 2a (A2aR) downstream signaling negatively regulates adaptive immune responses by limiting the function of effector T cells. Recent work from our lab has demonstrated that the A2aR-specific agonist blocks autoimmune arthritis that is mediated by GPI-specific KRN CD4 T cells. A2aR agonist caused a reduction of GC TFH cells that respond to autoantigen. Consistent with this, GPI-specific humoral immune responses were also reduced in A2aR agonist treated mice. To establish if the effect of A2aR agonist treatment on GC TFH differentiation was T cell intrinsic, CD4-Cre A2aR-floxed B6 mice were immunized with a protein complex containing a CD4 T cell antigen (2W1S peptide) and B cell antigen (PE). Polyclonal 2W1S/I-Ab-specific CD4 T cells and PE-specific B cells were then monitored in the presence or absence of T cell-specific A2a receptors. Our data show that in the absence of T cell-specific A2a receptors, agonist treatment fails to influence GC TFH cell differentiation. Therefore, A2aR downstream signaling can be stimulated within autoreactive CD4 T cells during their encounter with self antigen, and can serve to limit the differentiation of dangerous GC TFH cell effectors. Ongoing experiments are working to identify the T cell-intrinsic mechanism by which A2aR signaling inhibits GC TFH cell generation.
Targeting the phosphatidylinositol 3-kinase signaling pathway to inhibit pathogenic B cells in systemic lupus erythematosus (SLE)
Authors: Yin Catherine C , Trigunaite Abhishek , Dinh Dominic , Yiu Ying , Lannutti Brian J , Stein Paul L 
Published: January 2023

Abstract
Systemic Lupus Erythematosus (SLE) is an autoimmune disease with high levels of autoreactive B cells and circulating anti-nuclear autoantibodies. Circulating antibody-antigen immune complexes deposit in tissues, including the kidney, causing chronic inflammation and irreparable tissue damage. The hematopoietic system expresses a unique isoform of the phosphatidylinositol 3 kinase (PI3K) catalytic subunit, termed delta (PI3Kδ). It is critical for B cell survival and function, and its inhibition results in impaired antibody production. We hypothesized that targeting PI3Kδ will decrease levels of circulating auto-antibodies in a mouse model of SLE and reduce disease pathology. This study shows that a clinically utilized small molecule inhibitor of PI3Kδ (GS-9820) significantly inhibits naïve B cell differentiation into antibody secreting plasma cells as well as B cell proliferation in vitro. Furthermore, in the (NZBxNZW)F1 mouse model of SLE, treatment with the PI3Kδ inhibitor reduced autoantibody levels to background and increased overall survival. Within 2 weeks of treatment animals showed a marked reduction of germinal center B cells and T follicular helper cells (Tfh). The decrease in autoantibody levels ultimately prevented kidney damage by reducing immune complex deposition and complement fixation. Current treatments for lupus predominantly utilize systemic immunosuppressive drugs which have severe side effects. Since PI3Kδ plays a predominant role in B cells, our data suggests a clinical PI3Kδ inhibitor can be a therapeutic for lupus, potentially reducing autoantibody levels and associated pathologies. This therapy can result in better disease management and quality of life for lupus patients.
The role of IL-10 in B-cell chronic lymphocytic leukemia cell survival
Authors: Alhakeem Sara Samir , McKenna Mary Kathryn , Gachuki Beth W , Rangnekar Vivek R , Byrd John C , Muthusamy Natarajan , Bondada Subbarao 
Published: January 2023

Abstract
B-cell chronic lymphocytic leukemia (B-CLL) is characterized by the progressive accumulation of abnormal lymphocytes in the periphery. Typically the disease progression is slow, but as the number of leukemic cells increases, they interfere with the production of other important blood cells, causing the patients to be in an immunosuppressive state. To study B-CLL we use cells from the transgenic Eμ-Tcl1 mouse, which spontaneously develop B-CLL. Previously we showed that Eμ-Tcl1 CLL cells produce an anti-inflammatory cytokine, IL-10, constitutively. Here we studied the role of IL-10 in CLL cell survival in vitro and the development of CLL in vivo. We found that neutralization of IL-I0 using anti-IL-10 antibodies or blocking the IL-10 receptor (IL-10R) using anti-IL-10R antibodies did not effect the survival of CLL cells in vitro. When we adoptively transferred Eμ-Tcl1 cells into IL-10R KO mice, we found that cells grew at a slower rate in IL-10R KO mice vs. wild type mice. We also found that there was a significant reduction in CLL cell engraftment in the spleen, bone marrow, peritoneal cavity and liver of the IL-10R KO mice. Further studies revealed that IL-10 could be playing a role in the tumor microenvironment possibly by affecting anti-tumor immunity. This was seen by a reduction in the activation of CD8+ T cells as well as a significantly lower production of IFN-γ by CD4+ T cells purified from CLL-injected WT mice in compare to the IL-10R KO injected mice. In current in vivo studies, CLL growth will be monitored in WT mice after IL-10 neutralization using anti-IL-10 monoclonal antibody to further elucidate the role of IL-10 in CLL development. These studies demonstrate that CLL cells suppress host anti-tumor immunity via IL-10 production.
Caspase-1 from MDSC promote MyD88 dependent carcinogenesis that is T-cell independent
Authors: Zeng Qi , Qualliotine Jesse R , Blosser Lee , pardoll Drew , Kim Young 
Published: January 2023

Abstract
Myeloid-derived-suppression cells (MDSC) are functionally defined to suppress T-cells in their primary means of immune evasion mechanism in cancer. However, we have discovered that MDSC can have direct, T-cell independent pro-carcinogenic effect on tumor cells. Sorted monocytic CD14+/CD11b+/HLA-DRlowMDSCs from head and neck squamous cell carcinoma (HNSCC) patients were found to increase the proliferation index of HNSCC cells. This induction of tumor proliferation was not dependent on MDSC-tumor cell contact. Exome analysis showed that these human MDSC from cancer patients expressed high levels of inflammasome complex, and supernatant from the MDSCs were found to secrete IL-1b and IL-18. When we probed the functional significance of these inflammasome complex, we found that MDSC’s promotion of tumor proliferative index of the tumor was found to be caspase-1 dependent. To test this in vivo, T-cell depleted caspase-1 null mice showed significant decrease in tumor growth rate. To confirm the importance of myeloid inflammasome signaling in carcinogenesis, we suppressed MyD88 gene in tumor cell line Cal27 and found that the ability of MDSC to promoting tumor proliferation is diminished. Taken together, our findings demonstrate that tumor infiltrating MDSCs may play a prominent role in chronic inflammation associated carcinogenesis.
Positive Feedback Loop between B cells/plasma cells and Macrophages Promote M2 Macrophage-Elicited Hepatoma Progression
Authors: Kuang Dong-Ming 
Published: January 2023

Abstract
Tumor progression has been recognized as the product of an evolving crosstalk between different cell types within tumor and its stroma. However, the crosstalk between humoral immunity and innate immunity within human cancer microenvironments is poorly defined. We show that infiltration of plasma cells orchestrates the differentiation and function of protumorigenic macrophages in human hepatocellular carcinoma (HCC): specialized polarized immunoglobulin G (IgG)-secreting plasma cells in HCCs trigger the differentiation of protumorigenic M2b polarized macrophages. Reciprocally, autocrine interleukin 6-elicited-interferon-inducible protein 10 (IP-10) and membrane-bound intercellular cell adhesion molecule-1/vascular cell adhesion molecule (ICAM-1/VCAM) expressed by macrophages selectively induces long-lived IgG-secreting plasma cells, forming a positive feedback loop, in coculture systems and mice. Plasma cell infiltration determines macrophage-associated clinical outcome of HCC patients. These findings suggest that bidirectional communications between macrophages and B cells in cancer microenvironments support humoral immunity-elicited myeloid cell suppression and disease progression.
Time-course analysis of SHIP-1 modulation and expression in a pancreatic cancer model
Authors: McGill Andrew Robert , Ghansah Tomar , Ortiz-Rivera Ivannie , Iclozan Cristina 
Published: January 2023

Abstract
Pancreatic cancer (PC) is an aggressive disease with minimally effective therapies due to immunosuppression. Src Homology Inositol Phosphatase (SHIP-1) expression is essential in regulating myeloid derived suppressor cell (MDSC) and T regulatory cell (Treg) homeostasis and function, which can positively or negatively impact antitumor immunity. Inflammatory factors play an important role in the regulation of SHIP-1 expression. We demonstrated in our pancreatic cancer tumor bearing mice (TB) that SHIP-1 gene and protein expression is diminished in lymphoid tissues, correlating with an expansion of MDSC and Treg percentages compared to control mice (CTRL). These TB mice are generated via subcutaneous injection with Panc02 cells. Furthermore, we showed that inflammatory factors were elevated in TB mice compared to CTRL mice. In this study we sought to pinpoint the exact time when SHIP-1 expression was reduced, in correlation with the expansion of MDSC and Treg, along with the increase in production of inflammatory factors in TB mice. To evaluate the loss of SHIP-1, weekly time-course experiments were performed via collection of peripheral blood (PB) and lymphoid tissues for a total of 4 weeks. Preliminary data indicates a reduction of SHIP-1 expression two weeks post tumor inoculation, which correlated with the expansion of MDSC and Treg percentages and an increase in tumor and spleen weights in TB mice compared to CTRL mice. Also, PB from TB mice showed a weekly increase in the production of inflammatory factors compared to CTRL mice. The results from this study may further establish SHIP-1 as a potential therapeutic target that may help combat PC in humans.
CXCL9, CXCL10 and IFNγ favor the accumulation of infused T cells in tumors following IL-12 plus doxorubicin treatment
Authors: Hu Jiemiao , Bernatchez Chantale , Xia Xueqing , Xu Zihang , Hwu Patrick , Li Shulin 
Published: January 2023

Abstract
The infiltration of cytotoxic CD8+T cells suggests a positive prognosis in a number of established tumors. T cell therapy is rapidly growing in the past decade, and achieved big success in treating hematological tumors. Despite autologous TIL infusion made remarkable breakthroughs in treating refractory melanoma, the highest respond rates are only around 50%. Therefore, approaches which guide TILs to reach tumor sites more efficiently are to be developed. We employed the approach of IL-12 plus doxorubicin prior to T cell infusion in a murine lung cancer model and a human xenograft model. IL-12 plus doxorubicin were administered when tumors reached 5–7 mm in diameter. One day after, immune competent T cells were transferred intravenously into tumor bearing NSG mice. We also used the same strategy to infuse autologous TILs to human melanoma xenograft tumors. Not only did our approach increase the numbers of infiltrated CD8+T cells in tumors, and more significantly, it raised the ratios of immune stimulatory and immune inhibitory markers. As a result, large number of tumor cells undergoes apoptosis, along with delayed tumor development and extended survival time. The mechanism study revealed that T cell-attracting chemokines CXCL9 and CXCL10 induced by doxorubicin accounted for the recruitment of T cells to tumors, and the tumor-specific upregulation of IFNγ following IL-12 signaling initiate the positive feedback to stimulate T cell proliferation. Here, we showed the approach of IL-12 plus doxorubicin followed by murine T cell and human TIL infusion yielded striking response in murine and human xenograft solid tumors. In light of our findings, our approach might broaden the application of T cell therapy in a wider variety of solid tumors.
In vivo antigen-specific activation of CD8 T cells following radiation therapy can be monitored using Nur77-GFP transgenic mice
Authors: Uhde Lauren K , Moran Amy E , Crittenden Marka R , Gough Michael J 
Published: January 2023

Abstract
Current studies monitoring T cell infiltration within tumors using surface markers (i.e. CD69, CD25) are limited by their inability to distinguish activation through the T cell receptor (TCR) or through other inflammatory pathways. Here we use a reporter mouse expressing green fluorescent protein (GFP) with the immediate early gene Nr4a1 (Nur77), in which the level of GFP expression corresponds only to the strength of TCR stimulation. Research indicates that radiation therapy (RT) modifies tumors for improved lymphocyte infiltration and T cell killing. We investigated whether the proportion of antigen-specific infiltrating CD8 T cells increased following irradiation, hypothesizing that RT increases this number in irradiated tumors.
We bred C57BL/6J-Tg(Nur77-GFP) mice with FVB/N-Tg(MMTV-PyMT) spontaneous mammary tumor mice to yield GFP-expressing F1 mice with and without the MMTV-PyMT oncogene. Age-matched tumor-bearing mice were left untreated or treated with 10 Gy CT-guided RT to the mammary tumors. Alternatively, untreated tumors were harvested, transferred into Nur77-GFP+ MMTV-PyMT- littermates, and then treated. Tumors were harvested one week later.
Antigen-specific (Nur77-GFP+) CD8 T cells could be detected in both spontaneous and transplanted tumors, indicating an endogenous adaptive immune response to tumor-associated antigens. Our hypothesis proved false as no difference was found in the proportion of GFP+ T cells following RT in either the parental (p=0.727) or the transferred (p=0.803) tumors compared to untreated controls. These data suggest that improvements in T cell mediated tumor killing following RT are due to changes in quality, not quantity, of antigen-specific T cells.
sCYLD expression leads to CLL in mice and men
Authors: Hövelmeyer Nadine , Hahn Matthias , Reissig Sonja , Müller Claude , Wunderlich Thomas , Waisman Ari 
Published: January 2023

Abstract
A tightly regulated NF-κB pathway is very important for B cell homeostasis. Aberrant activation of NF-κB is involved in the development of chronic lymphocytic leukemia (CLL). The deubiquitinating enzyme CYLD, acts as a negative regulator of NF-κB by removing K63-linked ubiquitin chains from its target proteins. Here, we show that the B cell specific deletion of full-length CYLD and expression of the shorter splice form (sCYLD) lacking the binding sites for TRAF2 and NEMO, leads to the dramatic expansion of CD5 positive B cells, a hallmark of CLL. These cells accumulate in the blood and lymphatic organs with age, and show characteristic up-regulation of typical CLL-markers such as ZAP-70 and Bcl-2. A20, another negative regulator of NF-κB targets some of the same proteins as CYLD, thereby potentially compensating for the lack of FL-CYLD. We crossed sCYLD mice to a B cell specific A20 knockout. In these mice, the CLL phenotype progresses more rapidly probably due to an increase of NF-κB activity, up to the point where 100% of the B cells are CD5+. These cells show oligoclonal expansion, infiltrate the liver and the lungs, and accumulate in all lymphatic organs. Interestingly, we could show that some human CLL patients also express sCYLD, whereas none of the healthy controls do. These findings indicate that sCYLD is a new risk factor for CLL and implies that disrupted alternative splicing of key NF-κB regulators lead to the development of CLL.
Regulation of peripheral node addressin in tumor-associated CD31+ vascular endothelial cells.
Authors: Rodriguez Anthony B , Peske J David , Woods Amber N. , Engelhard Victor H 
Published: January 2023

Abstract
Naïve T cells use peripheral node addressin (PNAd), normally found on lymph node (LN) high endothelial venules (HEV), to traffic into lymphoid organs. We previously reported that the vasculature of murine tumors expressed PNAd and CCL21, which supports infiltration and intratumoral activation of naïve T cells, in turn delaying tumor growth. PNAd expression on tumor vasculature depends on effector CD8+ T cells that secrete LTα3, which signals through TNFR on tumor-associated CD31+ endothelial cells. PNAd expression is low on tumor vasculature, suggesting that it might be regulated differently than PNAd on HEV. Using RT-qPCR, we found that most of the enzymes responsible for PNAd synthesis are expressed comparably in CD31+ cells from tumors and LN. However, the primary sulfotransferase responsible for the generation of the 6-sulfo sialyl Lewis X structure on PNAd HEV, GlcNAc6ST-2, is minimally expressed in tumors. Tumor CD31+ cells expressed equivalent levels of GlcNAc6ST-1, suggesting that it is responsible for low-level PNAd expression. Of the scaffolding proteins that make up PNAd, GlyCAM-1 was minimally expressed in tumor CD31+ cells, whereas all others were expressed comparably. To identify the components of PNAd biosynthesis in tumor CD31+ cells that are controlled by LTα3-TNFR signaling, we evaluated tumors from WT and TNFR1/2KO mice. GlyCAM-1 was the only assessed PNAd component that was ablated in TNFR1/2KO tumors. However, based on transcript levels, GlyCAM-1 accounts for only about 10% of the PNAd scaffolding proteins in tumor CD31+ cells. This suggests that TNFR signaling regulates additional PNAd biosynthetic components yet to be examined, or that it regulates one or more components at the level of protein translation.
Spleen actively recruits, maintains and expands hematopoietic stem and progenitor cells in tumor-bearing hosts
Authors: Zheng Limin , Wu Chong , Ning Huiheng 
Published: January 2023

Abstract
We recently found that circulating hematopoietic stem and progenitor cells (HSPC) from various cancer patients exhibit a generalized myeloid bias with a skew toward granulocytic differentiation. These circulating myeloid precursors are highly enriched in tumors and serve as an important link between dysregulated hematopoiesis and accumulated myeloid-derived suppressor cells (MDSC) in cancer patients. Here, we showed that, in various murine tumor models, spleen is significantly superior to bone-marrow in inducing expansion of both hematopoietic stem cells and discrete intermediary progenitors, with a skew toward myelopoiesis. The bone-marrow derived HSPC are actively recruited and maintained in the spleen of tumor-bearing mice, a process that is regulated by CCL2/CCR2 axis, but not CXCL12. Splenic HSPC from tumor-bearing mice exhibits significantly higher proliferative activity and gives rise to CD11b+Gr-1intLy6G− Ly6Chi multipotent monocytic cells, the committed progenitors and immediate precursors of MDSC. Accordingly, abrogation of splenic hematopoiesis synergistically enhanced the therapeutic efficacy of anti-PD-L1 treatment. Moreover, we found that hematopoietic precursors and myeloid cells are accumulated in the spleen of patients with various solid tumors. These data suggest that the spleen is an important extramedullary reservoir and source of myeloid progenitors. Identifying unique splenic signals that instruct myeloid cells and their precursors might provide a novel strategy for anticancer therapy.
Infiltrate of effector regulatory T cells predicts outcome in a cohort of New Zealand colorectal cancer patients – a pilot study
Authors: Kemp Roslyn , Hartstonge Kirsten A Ward , McCulloch Tim , Kamps Ann-Kristin , Cretney Erika , McCall John 
Published: January 2023

Abstract
Staging of patients with colorectal cancer is currently based on tumour morphology and does not take into account the complexity of the anti-tumour immune response. Early-stage colorectal patients are usually treated with surgery alone and are not recommended additional adjuvant therapy. Up to twenty-five percent of these patients have relapse of disease, indicating that the current staging does not accurately predict disease-free survival. The Immunoscore has been proposed to incorporate the T cell infiltrate in the tumour into current staging protocols to improve estimates of disease-free survival. However, T cell subsets are complex and therefore may have different effects on patient outcome. Immunofluorescence was used to analyse immune cell infiltrates in early stage (II) colorectal cancer patients and to compare those with recurrent and non-recurrent disease (n=33). CD3 and CD8 were used for the Immunoscore. FoxP3, Blimp-1 and CD3 were used to identify effector regulatory T cells. Patients with a high Immunoscore (high T cell infiltrate) had increased disease-free survival than patients with a low Immunoscore (low T cell infiltrate, Log-rank test p&gt;0.001). The ability to predict patient outcome was improved by measuring the infiltrate of CD4+FoxP3+Blimp-1+ cells (effector regulatory T cells, Log-rank test p&gt;0.001). Patients with a low Immunoscore but high infiltrate of CD4+FoxP3+Blimp-1+ cells at the centre of the tumour had increased disease-free survival than those with a low Immunoscore and a low infiltrate of CD4+FoxP3+Blimp-1+ cells. These results show that incorporating the complexity of the local immune response into current practice may improve prediction of patient outcome in colorectal cancer.