bluuebunny/crossref_metadata_2025_split huggingface dataset:
Network-guided bioengineering of oncolytic immunovirotherapies for glioblastoma
Authors: Monie Dileep D. , Zhang Cheng , Correia Cristina , Ung Choong , Vile Richard G. , Li Hu 
Published: January 2023

Abstract
Glioblastoma is the most common and lethal primary brain tumor in adults, with a median survival less than 15 months despite current standard of care. Oncolytic immunovirotherapies (OVs) have shown promise in early clinical trials. OVs are engineered to specifically target cancer cells, trigger autophagic programmed cell death, and release tumor antigens in the context of T-cell activating cytokines. Cellular communication network factor 1 (CCN1) is an extracellular matrix protein expressed in 70% of glioblastomas that has been shown to drastically reduce OV efficacy, particularly herpes simplex virus type 1 (HSV-1). Our objectives were to decode protein-protein interaction (PPI) networks activated by CCN1, identify critical nodes in resistance networks, and use this analysis to design OVs that overcome CCN1-mediated resistance. We used NetDecoder to elucidate phenotype-specific PPI subnetworks in LN229 human glioblastoma cells with tetracycline-inducible CCN1 expression. Publicly available microarray data on CCN1-induced and control samples established differentially expressed genes, which served as sources in our PPI network to derive prioritized context-specific subnetworks. We found that 11 source genes collaborate via 39 deep nodes to confer OV resistance to CCN1-expressing glioblastomas. Of these, a router (IKBKE) and a sink (YBX1) have been previously implicated in glioblastoma pathogenesis. We conclude that autophagy regulator HSP90AA1, a critical node, may be targeted to improve OV efficacy in CCN1-expressing glioblastomas. Furthermore, WebGestalt overrepresentation analysis of subnetwork nodes suggests that oncolytic adenovirus may be more effective than HSV-1 as a synthetic biology chassis.
Immunogenicity comparison of neoantigen vaccines through different delivery platform
Authors: Wu Pinyi , Jiang Haitao , Shen Hao-chun , Tao Mi-Hua 
Published: January 2023

Abstract
Neoantigens are promising cancer vaccine candidates because they’re cancer-specific and can be predicted from the patient’s genomic data. A major challenge for developing potent neoantigen vaccines is the low immunogenicity of neoepitopes. DNA vaccines can deliver multiple epitopes and cytokines as an adjuvant in a single plasmid, and its immunogenicity can be further enhanced through heterologous prime-boost strategy. Here, we hypothesized utilizing DNA prime, adenovirus boost (refer to the DDA approach) strategy can improve the immunogenicity of neoantigen vaccines. To investigate whether vaccination through the DDA approach or DDA combine GM-CSF as adjuvant can improve the immunogenicity of neoantigen vaccines. Using IEDB analysis resource to predict and rank the top 21 MHC class I epitopes (short peptide) for the B16F10 tumor while 27mer peptides (long peptide) were synthesized to cover both MHC class I and class II epitopes. The 27mer neoantigen sequences of the selected 21 MHC class I epitopes were cloned into one plasmid and adenoviral vector with or without GM-CSF sequence linked by p2a. Mice were immunized through the DDA approach or peptides with polyI:C. In the peptide vaccine, the majority of the response were mediated by CD4+ T cells, only one peptide can induce CD8+ T cells response. For the DDA approach, 14% epitopes can induce CD8+ T cell response in mice immunized with DNA vaccine. Moreover, in the group with genetic encoded GM-CSF. it has significantly enhanced CD8+T cell response compare to the former, which dramatically improved the immunogenicity of neoantigen vaccines. Our preliminary data also showed that immunization of DNA vaccines significantly delayed tumor growth.
Modulation of interleukin 4 signaling increases the efficacy of vaccines against opioid use disorders and overdose
Authors: Crouse Bethany , Huseby-Kelcher April , Robinson Christine , Baehr Carly , Pravetoni Marco 
Published: January 2023

Abstract
Opioid use disorder (OUD) affects over 27 million people worldwide and contributes to 118,000 fatal overdoses each year. Vaccines against opioids offer a novel therapeutic strategy for the treatment of OUD, however their clinical efficacy may be limited to a subset of patients. To increase vaccine efficacy and minimize individual variability, our lab has shown previously that blockage of IL-4 increases overall anti-opioid IgG titers and induces IgG class switching, which correlates with greater efficacy in preventing opioid distribution to the brain. The mechanism behind the IL-4-mediated increase in vaccine efficacy is still unknown. We found that the increase in antibody titers is consistent for various anti-opioid vaccine formulation as well as the tetanus, diphtheria, and pertussis (TDaP) vaccine, suggesting this may be a broadly effective strategy to increase vaccine efficacy. This effect was also similar between male and female mice. An increase in the number of germinal centers was seen after IL-4 depletion using both immunofluorescence and flow cytometry. NKT cells, a cell population known to secrete IL-4 during early germinal center formation, were not necessary for vaccine efficacy. Genetic deletions of IL-4, but not necessarily their downstream signaling cascade, increased vaccine efficacy to the same degree as the antibody-based depletion. Finally, RNA-sequencing suggests a possible role of antibody-mediated effector functions in the increase in vaccine efficacy. These pre-clinical data support the use of cytokine-based immunomodulators as molecular adjuvants to increase vaccine efficacy against challenging targets.
Cancer Vaccines in the Pacific Region
Authors: Sika-Paotonu Dianne 
Published: January 2023

Abstract
Pacific communities remain disproportionately affected by some cancers and stand to benefit from research that will contribute to improvements in health outcomes. Significant health inequalities already exist for Pacific Peoples with cancer, where the burden of cancer remains a growing public health concern. Emerging immunotherapeutic based strategies such as therapeutic cancer vaccines being developed to treat cancer, offer potential as one day becoming a frontline treatment for cancer. The purpose of this work was to facilitate appropriate engagement and discussion to explore the potential applicability of therapeutic cancer vaccines within the Pacific setting. As part of wider cancer related discussions and consultation activities, preliminary engagement efforts were made to understand the potential utility of therapeutic cancer vaccines for treating cancer in the Pacific context in Tonga. The need for developing stronger cancer immunotherapies was acknowledged. Within the Pacific setting, therapeutic cancer vaccines would need to be affordable with the appropriate infrastructure required to support their utility in place. Strong support was also expressed for developing technologies to support early cancer detection given the constrained resources in the Pacific Region setting and as cancer presentation in Tonga is usually late and with poor prognostic outcomes. Overall, therapeutic cancer vaccines remain a promising treatment option, however their future applicability within the resource constrained setting, would require further research development and the provision to ensure appropriate resourcing and infrastructure in place for support.
Enhanced functional properties of in vitro expanded lymph node derived human NK cells
Authors: Dogra Pranay , Chin Athena , Kubota Masaru , Matsumoto Rei , Thapa Puspa , Szabo Peter , Poon Maya M.L. , Farber Donna L. 
Published: January 2023

Abstract
Natural killer (NK) cells are innate immune cells with the inherent ability to directly kill tumor and virus infected cells. Due to their ability to kill cancer cells without any prior priming, and their role in preventing metastasis NK cells have since long been the choice for autologous adoptive cell transfer therapy in cancer. However, poor expansion potential of PBMC derived NK cells in vitro is a major roadblock preventing the widespread use of NK cells in immunotherapy. We found that human NK cells isolated from lymph nodes (LNs) express higher levels of genes encoding for stem-like transcription factors (TCF7, LEF1, MYC) compared to NK cells from blood, spleen, bone marrow (BM) and lung. Therefore, we hypothesized that NK cells isolated from LNs will show superior expansion potential in vitro. Flow cytometric analysis shows that LN derived NK cells express high levels of TCF1 protein ex vivo, and show greater proliferation compared to NK cells isolated from blood, spleen and BM following stimulation with IL-2 and IL-15 in vitro. We also observed that a significant frequency of LN NK cells expressed TCF1 even after expansion, suggesting preserved proliferation potential of these cells. Additionally, the expanded NK cells from LN acquired properties of mature, highly functional NK cells such as increased expression of CD16, CD57 and higher Granzyme B expression. Lastly, LN derived NK cells also demonstrate enhanced cytolytic activity in vitro after expansion. Taken together our results suggest that in vitro expanded NK cells from LNs are potentially efficacious anti-tumor agents and could be leveraged for the development of future generation of NK cell directed immunotherapies.
The alarmin cytokine IL-1a drives a feedback-amplification loop between dying tumor cells and inflammatory monocyte-lineage dendritic cells
Authors: Sharma Madhav D , Rodriguez Paulo C , Munn David H 
Published: January 2023

Abstract
Successful immunotherapy must transform the normally suppressive tumor microenvironment into a pro-inflammatory, immunogenic milieu. We show that this critical transformation depends on a previously unrecognized initiating signal delivered by the damage-associated “alarmin” cytokine interleukin-1a (IL-1a). Initially, tumor-intrinsic IL-1a was mobilized from dying tumor cells. This drove rapid local differentiation of a population of monocyte-lineage inflammatory dendritic cells (DCs). We have previously described these inflammation-inducible myeloid DCs in tumors (Sharma et. al, Immunity 48:91–106, 2018), where they serve as key antigen-presenting cells during multiple forms of immunotherapy and chemo-immuno-therapy. Once these inflammatory DCs were elicited by tumor-derived IL-1a, they rapidly re-activated anergic/unresponsive tumor-associated CD8+ T cells. Then DCs and T cells together produced reciprocal host-derived IL-1a, thus completing a potent self-amplifying feedback loop. If this IL-1a-driven feedback-amplification loop was disrupted – either by silencing IL-1a in the tumor cells; or ablating IL-1a in the host cells; or disrupting the IL-1-receptor on the inflammatory dendritic cells – then anti-tumor immune activation was lost across multiple forms of immunotherapy and chemotherapy. To restore the ability to initiate immune activation, the only cells that needed to respond to IL-1a were the specific population of inflammatory monocyte-lineage DCs.
Exploring mechanisms of tumor resistance to CAR T cell therapy in immunocompetent mouse models
Authors: Andrews Alex , Thurston Gavin , Kirshner Jessica R. , DiLillo David J. 
Published: January 2023

Abstract
Chimeric antigen receptor (CAR) T cell therapies have shown striking clinical efficacy in the treatment of hematological malignancies, but limited success so far against solid tumors, suggesting that solid tumors may harbor mechanisms of resistance. To investigate mechanisms of CAR T cell therapy resistance in solid tumors, we developed immunocompetent mouse models to explore immune cell interactions and the effect of an immunosuppressive tumor microenvironment on CAR T cell behavior. We generated murine CAR T cells against a model antigen that contained a CD3z intracellular signaling domain linked to either a CD28 or a 4-1BB signaling domain. We found that murine CAR T cells exhibited a predominantly central memory phenotype together with potent cytotoxic activity and antigen-dependent cytokine release in vitro. Further, we found that murine CAR T cells exhibited strong anti-tumor efficacy against both disseminated (EL4) and subcutaneous (MC38) murine tumors in vivo, whereas non-binding control CAR T cells had no anti-tumor effect. However, in both the disseminated and subcutaneous models, tumors were suppressed but not completely eradicated. Although murine CAR T cells possessing either CD28 or 41BB co-stimulatory domains demonstrated similar in vitro activities, they exhibited strikingly different efficacies and resistance mechanisms in vivo. Collectively, these results highlight the contributions of specific co-stimulatory signaling pathways to CAR T cell therapy in immunocompetent murine models and provide a platform to explore resistance mechanisms to CAR T therapy against solid tumors.
Cytokine Pre-activated γδT cells in Cancer Adoptive Immunotherapy
Authors: Liu Haiyan 
Published: January 2023

Abstract
Adoptive cell therapy harnesses the power of immune system by stimulating and expanding immune cells to combat cancer. The application of tumour-specific αβT cell-based therapy may be hindered by limited tumour antigens. γδT cells are promising candidates for cellular immunotherapy because of their abundant IFN-γ or IL-17 production and MHC-independent cytotoxicity against a broad spectrum of tumors. Numerous attempts to use γδT cells in cancer immunotherapy have been made and resulted in variable efficacy and an overall good safety profile. Better expansion strategies are needed to improve the efficacy of the clinical trials using γδT cell-based immunotherapies. In the current project, we aim to explore the efficacy of cytokine pre-activated γδT cells in cancer immunotherapy. Pre-activated γδT cells by a combination of cytokines were characterised for their surface activation marker expression, cytokine production, and cytotoxicity against tumour cells. We found that IL-12/18, IL-12/15/18, IL-12/18/21 and IL-12/15/18/21 are the most effective cytokine combinations for in vitro expansion of γδT cells in terms of activation and cytokine production. IL-21 upregulated their cytotoxicity against tumour cells in murine systems. All four combinations showed upregulated cytotoxicity of human γδT cells. These findings were extended to in vivo studies using murine hepatocellular carcinoma model.
Human cytomegalovirus preferentially infects early gestation placental macrophages and evades their antiviral immunogenicity through evasion of the type I IFN response
Authors: Johnson Erica L , Swieboda Dominika , Chakraborty Rana 
Published: January 2023

Abstract
Human cytomegalovirus (HCMV) is the leading cause of congenital viral infections. When a pregnant woman develops primary HCMV infection in early gestation, the risk of transplacental infection is ~40%. Studies have documented the presence of HCMV in placental macrophages (Hofbauer cells [HCs]) as a consequence of maternal viremia. However, the interplay between HCMV and placental macrophages (HCs) is poorly defined. With written informed consent, placentae were collected from 12 HIV-1/Hep B/HCMV seronegative women (&gt;18 years). HCs were exposed to human HCMV (TB40/E). qPCR, FACS, ELISA, and Western blot analysis determined the expression of activation markers, cytokines, antiviral genes, and host proteins. Here we found that HCs isolated from early gestation (15–23 weeks) placentae are more susceptible to HCMV infection than HCs isolated from term (&gt;39 weeks) placentae. HCMV infection of early gestation HCs led to a significant upregulation of activation markers, along with elevated secretion of proinflammatory cytokines, compared to HCMV-infected term HCs. In early gestation and term HC, HCMV rapidly induces the type I IFN pathway, leading to secretion of IFNs and strong induction of ISGs. However, HCMV diminishes type I IFN-mediated phosphorylation of STAT2, with early gestation HCs exhibiting the greatest level of inhibition. Our findings show that HCMV can subvert type I IFN signaling to support viral growth at the placenta, particularly during early gestation. Studying mechanisms used by viruses to prevent an immune response is of great importance for the development of new strategies to limit the sequelae of viral infections.
Comparison of Interferons and Other Biomarkers in Influenza and Healthy Donor Samples
Authors: Lavoie Thomas B , Schwartz Barbara , Kisiel Greggory , Panday Alok , Skup Kamil , Clark William 
Published: January 2023

Abstract
Toward an understanding of biomarkers for acute viral diseases we have examined Influenza serum in comparison to healthy donors. We determined the levels of Interferon (IFN) Alpha, Beta, Gamma as well as Neopterin and Beta-2 Microglobulin (B2M) by ELISA in the Serum of 38 Influenza and 65 healthy donors using commercial assays. We measured chemokines and proinflammatory cytokines as biomarkers for IFN Activity by electrochemiluminescence. Assays were performed according to the manufacturer’s protocol. IFN-Omega levels were determined using a newly developed ultra-sensitive single molecule assay sensitive to 0.04 pg/ml. Percentile stratification was by Mann-Whitney non-parametric testing and correlations were determined under Spearman conditions. None of the healthy donors exhibited quantifiable IFN-Alpha or Beta and only two had detectable levels of IFN-Omega. Within the Flu cohort, 68.5% of samples contain quantifiable IFN-Alpha and Omega and 39.5% had IFN-Beta. 79% of the Flu samples displayed IFN-Gamma levels above the 95th percentile determined from the healthy donor distribution. Neopterin, B2M, and CXCL-10 were all significantly elevated in the Flu cohort versus the healthy subclass. Other chemokines either showed no correlation or a mild negative correlation. There was a striking concordance between IFN-Alpha and Omega levels. To our knowledge this is the first study to measure IFN-Omega and a broad panel of other analytes in Flu samples. As such this study may provide a beginning to discriminate between different viral diseases.
B cell-intrinsic expression of Interferon Regulatory Factor 1 supports chronic gammaherpesvirus infection
Authors: Jondle Christopher Ned , Johnson Kaitlin , Uitenbroek Alexis , Sylvester Paul , Tarakanova Vera 
Published: January 2023

Abstract
Gammaherpesviruses are ubiquitous pathogens that are associated with multiple cancers, including B cell lymphomas. These viruses infect naïve B cells and drive a robust germinal center response to amplify the latent viral reservoir and establish life-long infection in memory B cells. It is the increase in mutagenic B cell differentiation caused by the robust gammaherpesvirus-driven germinal center response which is thought to be the primary cause of malignant transformation in viral-driven lymphomagenesis. The host and viral factors that selectively impact gammaherpesvirus-driven germinal center response are poorly defined. We found that global deficiency of the antiviral and tumor suppressive Interferon Regulatory Factor 1 (IRF-1) selectively promotes the gammaherpesvirus-driven germinal center response and expansion of the viral latent reservoir. To establish the degree to which the antiviral effects of IRF-1 are B cell-intrinsic, we generated mice with conditional deficiency of IRF-1. Unexpectedly, IRF-1 B cell-intrinsic function supports the establishment of chronic viral infection and the gammaherpesvirus-driven germinal center response. Indicating that the antiviral function of IRF-1 during gammaherpesvirus infection is mediated though its expression in non-B cell populations.
Conspiring with the enemy: IRF-3 supports latent gammaherpesvirus infection of germinal center B cells
Authors: Johnson Kaitlin E , Sylvester Paul , Aurubin Carlie , Tarakanova Vera 
Published: January 2023

Abstract
Gammaherpesviruses (GHVs) are ubiquitous pathogens that establish lifelong infections in their host. Importantly, these viruses manipulate B cell differentiation to establish long-term latency and are associated with a variety of B cell lymphomas. In a clever feat, GHVs infect naïve B cells and drive the infected B cells along with uninfected bystanders into the germinal center response, where the rapid expansion of B cells results in an exponential increase in the latent viral reservoir. Germinal center B cells are also thought to be the target of malignant transformation.
Type I Interferon (IFN), a major antiviral system of the host, is transcriptionally activated by several host factors, including Interferon regulatory factor 3 (IRF-3). IRF-3 restricts GHV lytic replication during acute infection. Importantly, nothing is known about the role of IRF-3 during chronic GHV infection that is almost exclusively represented by the latent viral life cycle. Additionally, no studies have examined the effect of IRF-3 on the GHV-driven germinal center response.
Unexpectedly and in contrast to the phenotype during acute infection, we discovered that IRF-3 deficiency attenuated the establishment of chronic GHV infection, revealing a a pro-viral role of IRF-3 during viral latency. Further, while there was no effect on germinal center B cell expansion in the absence of IRF-3, the efficiency of germinal center B cell infection by GHV was reduced. Current studies are examining how IRF-3 may be facilitating latent infection of germinal center B cells. This is, to our knowledge, is the first example of IRF-3 functioning in a pro-viral manner in the context of chronic virus infection.
B cell-intrinsic MHCII expression restricts bacterial dissemination from the gut and maintains metabolic tone
Authors: Roland Mary Melissa , Mohammed Ahmed Dawood , Jolly Amy , Kubinak Jason 
Published: January 2023

Abstract
The expression of major histocompatibility complex class II (MHCII) molecules on the surface of B cells is essential for cognate interactions with T cells and ultimately the generation of high affinity serum antibody responses. Serum antibody responses play an important role in limiting the ability of gut microbes to colonize the systemic compartment. This is important because bacterial dissemination from the gut can have severe physiological consequences ranging from life-threatening septicemia to chronic low grade systemic inflammation. Here we use a conditional knockout mouse model (B-MHCII−/− mice) to determine the physiological implications of loss of T cell dependent serum antibody responses due to B cell-intrinsic ablation of MHCII expression. Loss of MHCII expression on B cells in B-MHCII−/− mice results in a significant reduction in the generation of long-lived plasma cells in the bone marrow and reduced circulating levels of IgG1. Reduced levels of circulating IgG1 is associated with increased levels of bacterial dissemination from the gut into the systemic compartment, as B-MHCII−/− mice have significantly increased titers of anaerobic bacterial colony-forming units in their livers. Importantly, increased bacterial dissemination is associated with an inability of B-MHCII−/− mice to gain weight, suggesting that bacterial dissemination in B-MHCII−/− mice drives the development of a metabolic disorder. Collectively, our data imply that beyond MHCII’s role in infectious immunity, MHCII-mediated antibody responses also play a fundamental role in establishing benign symbiosis with resident microbiota to maintain proper metabolic physiology.