bluuebunny/crossref_metadata_2025_split huggingface dataset:
Selective inhibition of gelatinases mitigates T-cell receptor signaling in CD4+ T-cells resulting in reduced clinical severity in a murine model of Multiple Sclerosis.
Authors: Onwuha-Ekpete Lillian C. , Tokmina-Roszyk Dorota , Fields Gregg 
Published: January 2023

Abstract
Matrix metalloproteinases (MMPs) are a family of proteolytic enzymes that mediate the degradation of extracellular matrix components. The gelatinases, MMP-2 and MMP-9, have functions essential for normal physiological processes such as leukocyte trafficking, but their dysregulation is associated with various pathologies including Multiple Sclerosis (MS). During MS, CD4+ T-cells activated in the periphery penetrate the blood-brain barrier (BBB), recruit immune cells, initiate destruction of the myelin sheath, and cause axonal loss. Experimental Autoimmune Encephalomyelitis (EAE) is a well-established murine model of MS. In EAE, gelatinases are required for penetration of the BBB and generation of auto-antigens. Recent studies have demonstrated that they contribute to normal intracellular function of various cell types including antigen activated T-cells; however, their intracellular role in immune cell activation during EAE pathogenesis is not known. In our studies, we demonstrate that gelatinases are important for effective T-cell receptor (TCR) signaling. Upon activation, CD4+ T-cells lacking gelatinase activity demonstrated a reduced ability to express early activation markers, proliferate, produce cytokines, and undergo metabolic reprogramming. However, in the absence of TCR stimulation, CD4+ T-cells have no proliferative defects. In addition, RNA-seq analysis highlight key proteins impacted by gelatinase inhibition that are associated with the TCR signaling. Furthermore, EAE mice demonstrated reduced clinical severity following gelatinase inhibition. These results emphasize the importance of the gelatinases as therapeutic targets in CD4+ T-cell mediated autoimmune diseases.
Coordinated events following TLR-9 and CD122 signaling promote NF-kB/AKT/STAT5-dependent B-CLL clonal expansion
Authors: Mongini Patricia K. A. , Gupta Rashmi , Vergani Stefano , Allen Steven L. , Barrientos Jacqueline , Kolitz Jonathan , Rai Kanti , Chiorazzi Nicholas 
Published: January 2023

Abstract
B-cell chronic lymphocytic leukemia (B-CLL) clones express BCR specific for microbes and/or apoptotic cells and elevated TLR-9. In patients, B-CLL clonal expansion occurs within lymphoid tissues. We recently reported that CpG DNA (ODN-2006) and IL-15, found within stromal cells of CLL-infiltrated lymphoid tissues, manifest synergy in promoting in vitro B-CLL growth (J. Immunol 195:901–923, 2015). This study explores the mechanism responsible by using purified B-CLL from peripheral blood to assess the temporal requirements for IL-15; effect of ODN on expression of IL-15 receptors (IL-15Rα and CD122 (IL-2/15Rβ)); and IL-15-induced activation of AKT and STAT5. Experiments with CFSE-labeled B-CLL show that IL-15 is critical during a 20–36 h window after ODN priming. Neutralizing mAbs to IL-15 or CD122 fully abrogate IL-15-driven growth when added during this interval. RT-PCR/immunofluorescence studies show that ODN triggers rapid increases in mRNA/protein for IL-15Rα and CD122 that are blocked by IkBα inhibitor. Furthermore, ODN-primed B-CLL exposed to IL-15 manifest elevated pAKT(Ser473) and pSTAT5(Tyr694) levels. Both PI-3K/AKT and STAT5 pathways are functionally relevant, as indicated by growth abrogation by pharmacologic inhibitors, LY294002, pimozide or STAT5 Inh II. Importantly, activated STAT5 levels are high in cycling CFSE-labeled B-CLL; furthermore, extended divisions were blocked by delayed (day 4) administration of STAT5 inhibitors or neutralizing mAbs to IL-15/CD122. Together, findings show that ODN + IL-15-driven growth represents coordinated early functions of TLR-9 and CD122 as well as later CD122 signaling during clonal expansion. This synergy may help drive in vivo growth of B-CLL clones in patients.
TLR and CLR agonists induce anti-tumor B cell responses against peritoneal carcinomatosis
Authors: Dyevoich Allison , Haro Marcela , Haas Karen M. 
Published: January 2023

Abstract
Peritoneal carcinomatosis is a condition where primary tumors metastasize into the peritoneal cavity and induce malignant ascites. The median survival of patients is poor, averaging about twenty weeks post diagnosis. Due to the high mortality rate associated with this disease and the lack of curative treatments available, it is imperative that more effective treatments be developed for peritoneal carcinomatosis. The immune system plays an important role in tumor elimination, and one strategy currently being explored to treat malignancies involves leukocyte activation through pattern recognition receptors (PRRs), including Toll-Like Receptors (TLRs) and C-type Lectin Receptors (CLRs). Our data shows that mice treated with a TLR and CLR agonist are afforded significant protection when challenged with an aggressive ascites-forming mammary tumor cell line (TA3-Ha). However, when mice lack B cells, the protection is lost. Administration of the combined treatment results in a significant increase in proliferating, antibody-producing B cells within the visceral adipose tissue (VAT). Consistent with this, the treatment induces a significant increase in IgM and complement (C′) bound to tumor cells, both of which were determined to be critical players in the anti-tumor effects. In summary, our data demonstrates pathogen associated molecular patterns can induce rapid natural IgM production that elicits anti-tumor protection via C′ activation.
Myeloid derived suppressor cells (MDSC) and anti-MUC1 immunosurveillance in pre-malignancy and cancer
Authors: Ma Peiwen , Beatty Pamela , McKolanis John , Schoen Robert , Brand Randal , Finn Olivera J. 
Published: January 2023

Abstract
Recent work from our lab showed that in a colon cancer prevention trial of a tumor antigen MUC1 vaccine in patients with premalignant colon adenomas, those who did not make anti-MUC1 IgG, had higher pre-vaccination levels of circulating MDSC compared to vaccine responders. This was the first observation of increased MDSC in premalignancy. MDSC in premalignancy have not been compared to MDSC in cancer and our hypothesis is that there might be differences in the composition of various MDSC subpopulation and their immunosuppressive functions due to the shorter time of exposure to disease and differences in the disease microenvironment. We are testing this hypothesis on two cohorts of patient samples, premalignant and malignant colon and pancreas. In both cohorts we saw an increase in MDSC in premalignant and malignant disease over healthy controls. The colon premalignant group could be divided into MDSChighAnti-MUC1 IgGlow and MDSClowAnti-MUC1 IgGhigh confirming our previous observations that MDSC are impeding anti-MUC1 immune response in premalignancy as well therefore potentially facilitating progression to cancer. The pancreas cohort also showed increase in MDSC in patients with pancreatic cysts (IPMN), precursors to pancreatic cancer, as well as their suppression of anti-tumor immunity. Furthermore, we found increased levels of PGE2 and its metabolite in patients’ serum from both cohorts, which is closely related to MDSC proliferation and mechanism of suppression. While we do not see much difference in the MDSC phenotype and subpopulation composition, the immunosuppressive capacity of tumor MDSC appears to be greater. We are currently testing this observation in vitro in T cell suppression assays.
Synergy of an anti-HER2 ADC TAK-522 (XMT-1522) in combination with anti-PD1 monoclonal antibody (mAb) in a syngeneic breast cancer model expressing human HER2
Authors: Khattar Mithun , Traore Tary , Horton Kristin , Gallery Melissa , Brauer Pamela , Riceberg Jessica , Bodyak Natalya , Protopopova Marina , Zhang Qingxiu , Lowinger Timothy B. , Veiby Petter , Huszar Dennis , Wang Frank 
Published: January 2023

Abstract
Antibody-drug conjugates (ADCs) are a highly potent class of drugs that specifically target cancer cells expressing a tumor associated antigen. The ADC TAK-522 consists of a novel human IgG1 anti-HER2 monoclonal antibody and a novel, auristatin-based cytotoxic payload (Auristatin F-hydroxypropylamide, AF-HPA). An average DAR of twelve AF-HPA molecules is achieved via a biodegradable polymer conjugation platform. The free payload AF-HPA and TAK-522 induced immunogenic cell death (ICD) in vitro in multiple cell lines measured by cell surface expression of calreticulin using microscopy and flow cytometry. Furthermore, we developed a novel syngeneic breast cancer model expressing human HER2 at a relatively low antigen density. Treatment in this poorly immunogenic tumor model with TAK-522 but not Kadcyla showed significant inhibition of tumor growth in vivo. Importantly, a combination of anti-PD1 mAb and TAK-522 therapy substantially and synergistically enhanced the anti-tumor efficacy, resulting in complete responses in some mice. The frequency of complete responders was further increased when the two drugs were sequentially, rather than concurrently, administered such that TAK-522 administration was followed by anti-PD1 mAb therapy, suggesting an immunological mechanism with induction of immunogenic cell death by TAK-522, which may activate the adaptive immune system by releasing tumor specific antigens. TAK-522 is currently being tested in a phase-1b clinical trial in patients with advanced breast, lung and gastric cancer expressing HER2. Based on our data, TAK-522 represents a potential candidate for combination therapies with immune checkpoint modulators in patients with poorly immunogenic HER2 expressing tumors.
The immune response in fractionated radiotherapy schedules: Implications for combination immunotherapy
Authors: Battaglia Nicholas Griffin , Gerber Scott A. , Lord Edith M. 
Published: January 2023

Abstract
Radiotherapy (RT) is used to treat approximately half of patients with solid tumors. Though DNA damage induced by RT plays a role in limiting tumor growth, RT also elicits an adaptive immune response. This response has been well characterized in the context of high dose, ablative RT and is dependent on IFN-γ expressing CD8+ T cells. In contrast, little is known about the immune response following clinically relevant fractionated RT schedules. Additionally, recent work has demonstrated that increased utilization of glycolysis is essential for T cell effector function, particularly for increasing expression of IFN-γ, and competition for glucose in the tumor microenvironment may limit the anti-tumor immune response. Using the MC38 adenocarcinoma murine tumor model, we have examined the immune response following iso-effective ablative and fractionated RT schedules designed to have biologically equivalent doses. Our results indicate that IFN-γ levels and T cell activation are decreased whereas macrophage frequencies are increased after fractionated RT as compared to ablative RT, correlating with increased rates of tumor rebound. Interestingly, preliminary data shows that tumor cells and tumor associated macrophages have increased consumption of glucose as compared to T cells following RT, indicating that selectively targeting the metabolism of these populations may improve the anti-tumor T cell response by reducing competition for glucose. Further study of these populations’ metabolism following fractionated and ablative RT will provide insights as to how these pathways may be targeted to improve outcomes of existing treatment modalities. Supported by awards T32AI007285 from the NIAID and R01CA028332 from the NCI.
Immune effects of combinatorial repurposing drugs in refractory ovarian and colorectal cancer patients.
Authors: Marquez-Manriquez Juan P. , LUCERO-DIAZ PEDRO-ALEJANDRO , MONTIJO-FERNANDEZ LORENA , MATUTE-BRISENO JOSE-ANTONIO , MONTANO GEOBANNI TORRES , VERBURG MARK L. , Rosas-Delgado Martin-Orlando , CAMACHO-HERNANDEZ ALEJANDRO 
Published: January 2023

Abstract

Background
Some refractory cancer patients have a good Karnofsky despite refractory disease. We studied the potential immunomodulatory properties of approved drugs. We used fresh PBMC from refractory patients to study the immune effects of several drugs such as metformin, pidotimod, erdostein, esomeprazole, colchicine, bortezomib, gemcitabine, zoledronic acid and naproxen.

Methods
25 high-grade serous ovarian cancer (HGSOC) and 25 colorectal cancer (CRC) subjects were included after approved protocol. The inclusion criteria include Karnofsky 80–100%, complete CT scan, acute phase proteins, granzyme B ELISPOT and antigen-specific ELISA.

Results
We found after 24 months of treatment in HGSOC 80% of complete response (CR), 15% of stable disease (SD) and 5 % of pseudo-progressive disease (PPD). In CRC we had 50% of CR, 30% of SD and 20% of PPD. In the patients with CR there was an immunological correlation of CD8 persistent immune response by granzyme B ELISPOT in HGSOC and CRC (p=0.0001) and PR (p=0.001), respectively. The combination was well tolerated and after 10 months of stopping the treatment some patients have persistent CD8 specific immune response by ELISPOT and ELISA.

Discussion
The combination of daily oral metformin, colchicine, pidotimod, erdostein, and naproxen plus weekly low dose of intravenous (IV) esomeprazole (80 mg), bortezomib (0.5 mg/m2), gemcitabine (0.5 mg/m2) and zoledronic acid (100 mg) is clinically feasible, with limited clinical toxicity. We now understand the importance of preserving the CD8 immune response and the use of immune biomarkers such as antigen specific ELISA to improve the rational and generate new combinations to improve clinical outcomes in patients with refractory HGSOC and CRC.
Long Non-Coding RNAs Regulate Transcription of Lymphoma Oncogenes
Authors: Beri Nina , Pyfrom Sarah C. , Oltz Eugene M. , Payton Jacqueline 
Published: January 2023

Abstract
Non-Hodgkin Lymphoma (NHL) is the most common blood cancer in the U.S. Our analysis of gene regulation in &gt;100 NHL and normal B cell samples revealed a distinct profile of long non-coding RNA (lncRNA) expression. Few lncRNAs have been characterized, and there are no guidelines for functional prediction or categorization. Therefore, we developed a novel computational approach: Correlative Recurrent Expression of Predicted Elements (CREPE), which integrates -omics data to create a correlative regression model to predict lncRNA function. CREPE analysis revealed several NHL-associated lncRNAs that may regulate the expression of signaling proteins downstream of B-cell receptor activation. We highlight a multi-exon lncRNA that is highly expressed in NHL and has a top-ranked CREPE transcriptional regulatory score: AC074289.1. Consistent with a role in regulating transcription, qRT-PCR of subcellular fractions demonstrate nuclear localization and chromatin association (3.5–5X : cytoplasm). Expression of AC074289.1 is cell-type specific with 5–10X higher levels in B lymphoid compared to T or epithelial cell lines. AC074289.1 expression positively correlates with a neighboring gene, PELI1, which encodes Pellino 1, an E3 ubiquitin ligase that modulates NF-κb signaling in immune cells. NF-κb signaling also plays a significant role in NHL pathogenesis. Notably, high PELI1 expression is associated with more aggressive NHL. In summary, our global -omics study of normal and NHL samples identified new gene regulatory connections between lncRNAs and potential NHL oncogenes, including AC074289.1 and PELI1. This novel approach will accelerate our understanding of lncRNA function and may uncover new therapeutic targets in NHL.
Intratumoral CD56bright Natural Killer cells are associated with improved survival in bladder cancer
Authors: Mukherjee Neelam , Ji Niannian , Tomasini Maggie E. , Hurez Vincent , Curiel Tyler J. , Montgomery Maureen , Braun Andrew J. , Nicolas Marlo , Aguilera Marcela , Liu Qianqian , Ruan Jianhua , Svatek Robert S. 
Published: January 2023

Abstract
Antitumor immune responses are largely mediated by cytotoxic lymphocytes that recognize tumor-associated antigens presented in the context of a major histocompatibility complex class I molecule (MHC I). However, many tumors downregulate MHC I expression as a means of immune escape. Under these conditions, additional effector lymphocytes, such as natural killer cells (NK cells) which mediate non-MHC restricted cytotoxicity, provide antitumor defenses. Using flow cytometric analysis, we discovered that NK cells predominate among lymphocytes infiltrating human and carcinogen-induced mouse bladder cancer (BC). Using transcriptomics and clinical outcomes from the TCGA dataset we found that the presence of intratumoral NK cells is associated with increased survival after cystectomy, especially in low MHC class I expressing tumors. We validated this finding using a local BC cohort and determined that functional NK cells decline with increasing patient age. Using in vitro assays, we found that intratumoral NK cells from bladder tumors exhibit MHC class I dependent cytotoxicity against BC cells. Importantly, intratumoral CD56dim NK cells increase with higher pathologic stage and are less functional (cytotoxicity and cytokine secretion) than CD56bright counterparts. The presence of intratumoral CD56brightNK cells predicts improved patient survival independent of tumor stage. We conclude that intratumoral NK cells are functional and prognostically relevant in BC, but their presence and function is diminished with aging or tumor MHC class I. Intratumoral CD56bright NK cells are associated with better clinical outcomes whereas CD56dim NK cells are dysfunctional and associated with advanced BC.
Nanoemulsion adjuvant augments retinaldehyde dehydrogenase activity in dendritic cells and regulates expression of gut homing receptors on T cells
Authors: Farazuddin Mohammad , Goel Rishi R. , Landers Jeffery J. , Kline Nicholas J. , Toufaily Nour , Uppula Pradyumna , O’Konek Jessica J. , Baker James R. 
Published: January 2023

Abstract
Mucosal surfaces are the primary point of entry for most infectious agents. Therefore, induction of mucosal immune responses serves as the primary defense by preventing and clearing pathogens. In order to mount an effective immune response, secretory IgA and T cell homing towards mucosal surfaces are two very important factors. Conventional vaccines induce strong systemic immunity, but often fail to produce mucosal immune responses. Our group has developed an oil-in-water nanoemulsion which has been shown to provide protection against mucosal pathogens when administered as an intranasal vaccine adjuvant. In the present study, we demonstrate that intranasal immunization with nanoemulsion indirectly activates the retinaldehyde dehydrogenase in dendritic cells, leading to an increase in secretory IgA production as well as expression of α4β7 and CCR9 gut homing receptors on the mesenteric lymph node cells. Ex vivo stimulation of splenocytes from NE immunized animals established increase in Th1/Th17 cytokines while suppressing Th2, suggesting RALDH increase does not suppress Th1/Th17 response. Our nanoemulsion based adjuvant activates retinaldehyde dehydrogenase without possessing any active ligand and imprints T cells for gut homing without altering systemic immunity. These results provide new insights into the mechanism of our nanoemulsion adjuvant and have significant implications for the design of effective mucosal vaccines.
HIV vaccine mimicking the RV144 regimen tightly controls and ablates SHIV BaL.P4 infection in rhesus macaques
Authors: Hessell Ann Jones , Pandey Shilpi , Sutton William F. , Liu Lily , Kong Xiang-Peng , Haigwood Nancy Logan , Gorny Miroslaw K. 
Published: January 2023

Abstract
The RV144 human HIV-1 vaccine trial provided the first and only immunologic signal to define a correlate of reduced risk. This sole independent correlate of reduced risk of HIV infection among the &gt;150 variables studied, was the level of antibodies (Abs) reactive with the V1V2 region of HIV-1 Envelope protein. We designed vaccine/challenge experiments designed to mimic the RV144 vaccine trial to study the protective effects of vaccine-elicited immune responses in rhesus macaques (RM). Nine RM were co-immunized at weeks 0, 4, 12 and 20 intradermally with gp160 92TH023 and SIV gag DNA via gene gun together with gp120 A244 and MN proteins formulated in Adjuplex. Two weeks after the final immunization, all RM and naïve controls were challenged intrarectally with SHIVBaL.P4. Blood and mucosal secretions were collected weekly. Plasma viral load (PVL) and PBMC-associated VL were significantly different between controls and immunized RM (p=0.0091, p=0.0045, respectively). Time to infection was greater in immunized NHP (p=0.0235, Kaplan Meier). PVL in 5 RM were either undetectable or transient at 102–103 copies/ml. Midpoint titers of anti-V2 plasma binding antibodies (Abs) were ~1 Log10 lower compared to titers against cognate and heterologous gp140 and gp120. The vaccine regimen induced strong Ab responses with neutralizing activity that inversely correlated with VL to tightly control or ablate SHIV infection in 5 of the 9 immunized macaques. At necropsy no virus was detectable in lymphoid tissues. Efficacy based on this outcome is 55%, representing a milestone in pre-clinical vaccine protection. This study provides a strong basis to investigate mechanisms associated with tight viremia control, including antibody Fc-mediated activities.
Poxvirus subversion of B7-mediated T cell co-stimulation
Authors: Elliott Jabari I. , Wang Xiaoli , Piersma Sytse J. , Nelson Christopher A. , Yokoyama Wayne M. , Fremont Daved H. 
Published: January 2023

Abstract
Poxviruses encode a broad array of proteins that serve to undermine host immune defenses. Our group has been investigating a large sequence-diverse family of secreted poxvirus proteins that appear to share a conserved beta-sandwich fold, but differ in their binding specificities. Host proteins discovered to interact with this viral protein family include: chemokines, GM-CSF, IL-2, MHC class I, and GAGs. We have termed members of this superfamily; Poxvirus Immune Evasion (PIE) proteins, and there appears to be at least 20 distinct subfamilies. As it turns out, cowpox virus (CPXV BR) contains 10 PIE proteins, one of which is secreted from virally infected cells and specifically binds B7.1 (CD80) and B7.2 (CD86), two membrane proteins expressed on professional antigen presenting cells and activated T cells. We have termed this viral protein B7 Response Modifier (BRM) and demonstrated that it competes with the CD28 as well as CTLA4 receptors expressed on T-cells for binding to B7 proteins. However, at low concentration, BRM competes primarily with CD28 for binding to B7.2, consistent with the idea that cowpox uses BRM to undermine T cell activation but not checkpoint control. Quantitative interaction analysis reveals that BRM binds the ectodomain of B7 proteins with higher affinity than that reported for CD28 or CTLA-4. Functionally, BRM can potently disrupt T-cell proliferation and IL2 production co-stimulated by B7 proteins. Furthermore, supernatants of wild-type but not BRM deleted CPXV are capable of suppressing B7.2-mediated T-cell activation. In sum, our findings define a novel mechanism of viral immune evasion that highlights the role of CD28 co-stimulation in host defense of poxvirus infections.