bluuebunny/crossref_metadata_2025_split huggingface dataset:
Combination therapy of adoptive T cell therapy and immune checkpoint blockades engages distinct mechanisms in CD4+ and CD8+ T cells
Authors: Shi Lewis Zhichang , Gao Jianjun , Allison James P. , Sharma Padmanee 
Published: January 2023

Abstract
Adoptive transfer of tumor-reactive T cells (ACT) has led to significant clinical responses in hematological malignancies. However, its efficacy in solid tumors has been dismal, likely due to the immunosuppression imposed by the tumor microenvironment (TME) of solid tumors. A proven effective strategy to revert the immunosuppressive TME is immune checkpoint blockades (ICBs) including anti-CTLA-4 and anti-PD-1/PD-L1 that have been recently approved by FDA for cancer therapy. Here, using the orthotopic B16-F10 melanoma model, we combine ACT of PMEL-1 Tg+ CTLs that recognize the endogenous melanoma antigen gp100 with dual blockade of CTLA-4 and PD-1, the highly-pursued effective combinatorial ICB, to treat established tumors. Although ACT alone transiently suppresses tumor growth, complete tumor regression requires additional dual anti-CTLA-4 and anti-PD-1 blockade. Mechanistically, we demonstrate that the ICOS-Eomes-IFN-g axis in the transferred CTLs plays a predominant role in mediating the therapeutic effects of ACT and ICBs, distinct from the dominant ICOS-T-bet-IFN-g axis in CD4+ T cells that we previously identified. Our data provide direct evidence that combining ACT of CTLs with ICBs confers long-term protection to solid tumors, which largely depends on CTL-intrinsic expression of ICOS.
Multi-peptide cancer immunotherapy in combination with sorafenib
Authors: Marquez-Manriquez Juan P. , MONTANO GEOBANNI TORRES , VERBURG MARK L. , CAMACHO-HERNANDEZ ALEJANDRO , LUCERO-DIAZ PEDRO-ALEJANDRO , MONTIJO-FERNANDEZ LORENA , VILLALOBOS-MOLINA PERLA-GABRIELA , Hinojosa-Martinez Simon , VERDUGO-VILLASENOR ALEXIS , MATUTE-BRISENO JOSE-ANTONIO 
Published: January 2023

Abstract

Background
Little is known why most of the cancer immunotherapies failed despite good results in pre-clinical studies. We believe that if we focus on clinically relevant multi-proteins to immune-target simultaneously in combination with drugs with potential immune properties we may improve the clinical outcomes.

Methods
12 proteins overexpressed in several human tumors and associated with prognosis were identified. Indirect ELISA (IgA+ IgM + IgG) and ELISPOT was used to evaluate immunity proteins in 50 cancer patients and 50 controls. Immunohistochemistry (IHC) staining was done for proteins and CD8 T-cell quantitation. Peptides that were highly immunogenic by ELISA and ELISPOT were formulated into multi-peptide immunotherapy and with low dose of oral sorafenib. Patients treated with active progressive disease 6 months, 12 times were monitored biweekly to evaluate the immune response.

Results
Serum responses for all positive antigens were significantly elevated in advanced cancer patient sera when compared to donor controls (Bcl-2 p=0.001, survivin p=0.0001, EGFR P=0.005, Fascin-1 p=0.0001, Sox2 p&lt;0.0002), RCAS1 p= 0.004, VCP = 0.05 and Ape-1 (p=0.0001). ELISPOT screening yielded epitopes that were immunogenic in advanced cancer patients. Metastatic areas of liver and lungs in advanced cancer patients were significantly inhibited after treatment with the multi-peptide immunotherapy and sorafenib.

Discussion
Advanced cancer is still immunogenic and overexpressed proteins involved in clinical relevant pathways can serve as specific active immunogens. These data could be the proof of principle for the development of multi-peptide immunotherapy in combo with drugs with immune properties such as sorafenib.
A B Cell Lymphoma-Associated LncRNA Modulates BCR-Mediated Calcium Signaling
Authors: Payton Jacqueline , Pyfrom Sarah , Luo Hong , Oltz Eugene M. 
Published: January 2023

Abstract
Long non-coding RNAs (lncRNA) act as transcriptional regulators, scaffolds, and signaling modulators, but their role in normal or malignant lymphocytes is unknown. We identified lncRNAs with altered expression in &gt;100 human Non-Hodgkin Lymphoma (NHL) and normal B cell samples. One of these lncRNA genes is upstream of PLCG2 and parallels its expression, but the transcript is localized in the cytoplasm, making transcriptional regulation of PLCG2 unlikely. As expected, knock-out (KO), knock-down (KD), or over-expression of lncRNA-PLCG2 did not affect PLCG2 levels. PLCG2 is a B-cell specific phospholipase C enzyme that stimulates Ca2+ signaling after BCR activation. We assessed Ca2+ signaling via IgM stimulation of the BCR in multiple lncRNA-PLCG2 KO/KD NHL cell lines and observed defects in Ca2+ efflux from the ER and influx through Orai channels. To identify lncRNA-PLCG2 interacting proteins, we performed RNA pull-down experiments using sense (S) and anti-sense (AS, control) lncRNA-PLCG2 as bait incubated with B cell lysates. Mass spectrometry of eluted proteins showed several proteins significantly enriched in S versus AS, including PLD1, DICER1 and DHX9; we confirmed these by Western blot. We next performed RNA-binding protein Immunoprecipitation (RIP) using antibodies for PLD1, DHX9 and DICER1, which showed 2–10-fold enrichment of lncRNA-PLCG2 compared to IgG isotype control. Ongoing studies are mapping lncRNA-PLCG2-protein interactions and evaluating the impact of lncRNA-PLCG2 on PLD1 activity. Taken together, these results suggest that lncRNA-PLCG2 modulates BCR-mediated Ca2+ signaling via interaction with BCR downstream signaling proteins, a previously unrecognized mechanism that may promote lymphomagenesis.
Mapping the transcriptome and epigenomic landscape of HDAC-inhibitor resistant CTCL
Authors: Andrews Jared , Schmidt Jennifer , Payton Jacqueline 
Published: January 2023

Abstract
Epigenetic alterations deregulate gene expression and are a significant contributor to cancer pathogenesis. Unlike gene mutations, epigenetic changes are reversible, and this distinction has been exploited therapeutically for Cutaneous T-cell Lymphomas (CTCL). Histone deacetylase inhibitors (HDACi) are FDA-approved; however, two-thirds of patients do not respond to HDACi. Therefore, we are addressing this gap by 1) establishing new techniques to identify HDACi response elements from all stages of CTCL and 2) developing targeted epigenetic modifiers (TEM) as a novel precision therapy.
Our key innovations in this study are the generation of targeted epigenetic modifiers (TEM) as potential therapeutics and the development of a technique called Ultra-Low Input Chromatin Immunoprecipitation (ULI-ChIP) that enables epigenome-wide profiling of histone modifications in 10,000–30,000 cells. We are utilizing this method to identify recurrently altered regulatory elements in HDACi-resistant CTCL patients, which, in conjunction with RNA-seq data, allow us to determine epigenomic and transcriptomic states that predispose patients for resistance to these treatments.
We have identified several regulatory elements upstream of CXCR4, a chemokine receptor with known roles in cell survival and metastasis in B cell lymphomas and T cell leukemias, that are dysregulated in HDACi resistant patients. Similar loci were also found near key transcription factor (FOXP1) and anti-apoptotic genes (BCL2). The most promising HDACi response elements will be targeted in CTCL cells using locus-specific epigenetic modifiers to validate and evaluate the potential of each locus to be further developed for TEM protein therapeutics.
Unique molecular identifiers of indolent versus aggressive phenotyping in non-Hodgkin lymphoma: spotlight on SMZL.
Authors: Robinson Jacob E. , Cutucache Christine E. 
Published: January 2023

Abstract
Splenic marginal zone lymphoma (SMZL) is an indolent, non-Hodgkin’s lymphoma that lacks clear genotypic classification. While most cases progress slowly, approximately 30% of cases will become aggressive or undergo transformation to a more lethal lymphoma. The purpose of this study was to characterize the molecular profiles of SMZL cases compared with healthy B-cells and other B-cell lymphomas (BCL) in an effort to delineate indolent versus aggressive presentations. We conducted a meta-analysis of previously published gene expression data in order to identify genes most dysregulated in SMZL. We compared gene expression datasets among SMZL, similar B-cell neoplasms (all B-cell lymphomas), and healthy B-cell controls in order to extract a SMZL-specific, indolent phenotype profile. As a result, we observed a unique profile of genes upregulated in SMZL that are involved in immune defense (inclusive of leukocyte chemotaxis), motility (inclusive of lamellipodium assembly), cell proliferation, as well as other mechanisms. Of these, the most upregulated genes in SMZL were CXCL6, KAZN, NTN4, CD5L, AIF1L, and CD36. Additionally, 20 key markers of potential indolence were identified, with the largest expression differences seen in ABI3BP, GPNMB, CCL19, and ZC3H7B. Further investigation of these genes and their resultant impacted pathways will be evaluated for diagnostic and prognostic significance using immunohistochemistry, and hypothesized targets evaluated in vitro. Ultimately, we expect that the translation of these results will assist with patient staging in SMZL.
Glycolipid stimulation of invariant NKT cells mobilizes precursors of mature NK cells and potentiates their participation in immune surveillance against metastatic cancer.
Authors: Choi Joshua , Chan Cindy , Lesage Sylvie , Haeryfar S.M. Mansour 
Published: January 2023

Abstract
Precursors of mature natural killer (pre-mNK) cells, initially called IFN-producing killer dendritic cells, have been recently characterized as a novel intermediate in NK cell differentiation. Typified by a unique B220+NK1.1+CD11c+MHCII+ phenotype, pre-mNK cells exhibit prolific anti-tumor cytotoxicity while retaining the ability to present antigens thereby activating neighbouring T cells. Invariant NKT (iNKT) cells are another population highlighted for their potential in anti-cancer immunity. They are activated very early and play an important role in transactivating downstream effectors, such as NK cells. The extent to which iNKT cells can activate pre-mNK cells is unknown. We hypothesized that iNKT cells are able to activate pre-mNK cells and potentiate their anti-tumor properties. Wildtype C57BL/6 mice were injected i.p. with the iNKT cell superagonist, α-galactosylceramide (αGC), and various lymphoid tissues were harvested after 5 days for phenotyping or cytotoxicity assays. We have shown, for the first time that iNKT cell activation via αGC results in robust expansion of pre-mNK cells in the spleen, lung and most notably, in the liver. These cells exhibited cytotoxic activity against YAC-1 thymoma and B16 melanoma cancer cells via the granule exocytosis pathway and significantly contributed to overall NK cytotoxic activity in vivo. The anti-cancer responses due to αGC activation have been well documented; however, the contribution of pre-mNK cells in these responses have never been shown. Our findings demonstrate that pre-mNK cells rapidly expand due to iNKT activation while retaining their capacity to kill tumor targets. This may suggest a novel mechanism of targeting pre-mNK cells in anti-cancer therapies.
A distinct human NKp30+FcɛRIγ+CD8+ T cell population exhibiting high NK-like anti-tumor potential
Authors: Correia Margareta P. , Stojanovic Ana , Bauer Katharina , Juraeva Dilafruz , Tykocinski Lars , Lorenz Hanns-Martin , Brors Benedikt , Cerwenka Adelheid 
Published: January 2023

Abstract
CD8+ T cells are considered prototypical cells of adaptive immunity. Here, we uncovered a distinct CD8+ T cell population, expressing the activating NK receptor, NKp30, in peripheral blood of healthy individuals. We revealed that IL-15 could de novo induce NKp30 expression in a population of CD8+ T cells, and further drive their differentiation towards a broad innate transcriptional landscape. The adapter FcɛRIγ was concomitantly induced, and shown to be crucial to enable NKp30 cell surface expression and function in CD8+ T cells. FcɛRIγ de novo expression required promoter demethylation and was accompanied by the acquisition of the signaling molecule Syk and the “innate” transcription factor PLZF. IL-15-induced NKp30+CD8+ T cells exhibited high NK-like anti-tumor activity in vitro, able to synergize with TCR-signaling. Importantly, this population potently controlled tumor growth in a preclinical xenograft mouse model. Our study, while blurring borders between innate and adaptive, reveals a unique NKp30+FcɛRIγ+CD8+ T cell population with high anti-tumor therapeutic potential.
Differential T follicular helper cell responses induced by candidate HIV vaccine strategies utilizing ALVAC versus Ad5 vectors
Authors: Auclair Sarah , Soong Lynn , Hu Haitao 
Published: January 2023

Abstract
The development of a safe and effective vaccine against Human Immunodeficiency Virus (HIV) remains a major priority in global health research. Several candidate HIV vaccines have undergone late-stage clinical trials in recent years, several of which utilized non-replicating viral vectors based on canarypox (ALVAC) or human adenovirus (Ad5.) Thus far, the only trial to show moderate (31.2%) efficacy in preventing HIV infection is the RV144 trial, which utilized an ALVAC prime/protein boost strategy. Subsequent analyses showed that protection from HIV infection correlated with the production of IgG3 antibodies directed against the highly conserved V1V2 loop of the HIV envelope (Env) protein, and was abrogated by the production of Env-specific serum IgA antibodies. Although the ineffective Ad5-based vaccines also induced strong Env-specific antibody responses, they failed to induce protective IgG3 and/or V1V2-specific antibodies. To better understand the mechanisms underlying the differential antibody profiles generated by these two vectors, we measured the frequency and functional phenotype of follicular T helper-like cells found in the peripheral blood of vaccine recipients (pTfh). We found that subjects who received an ALVAC prime/protein boost vaccine regimen had higher levels of Env-specific pTfh cells than subjects who received a DNA prime/Ad5 boost regimen, and that these pTfh cells have enhanced ability to induce B cell activation and class switching compared to those found in Ad5-based vaccine recipients. We hypothesize that the higher frequency and functionality of these ALVAC-induced pTfh cells contributes to the uniquely protective antibody response generated by ALVAC prime/protein boost vaccination.
Induction and relationship of HIV Envelope-specific B cells in the peripheral blood and bone marrow following vaccination in humans.
Authors: Kobie James , Basu Madhubanti , Piepenbrink Michael , Francois Czestochowa , Roche Fritzlaine , Fucile Christopher , Rosenberg Alexander , Liesveld Jane , Keefer Michael 
Published: January 2023

Abstract
Induction of long-lived plasma cells producing protective HIV-1 Envelope (Env)-specific antibody (Ab) is a primary goal of HIV vaccine strategies. However, vaccine-induced Env-specific human plasma cells have not yet been identified. In an effort to do so, samples were obtained from HVTN 105, a phase I trial in which participants were immunized with the same bivalent gp120 protein, AIDSVAX B/E, as used in RV144, although combined with a DNA immunogen (instead of ALVAC-HIV) in various prime/boost strategies. Participants who received a boosting regimen that included AIDSVAX B/E had robust peripheral blood plasmablast responses as measured by Env-specific ELISpot (n=21) and flow cytometry (n=20). The Env-specific immunoglobulin repertoire of the plasmablasts, assessed by monoclonal Ab generation (&gt;110 mAbs total from 15 participants), was dominated by VH1 gene usage (~60%, VH1-2&gt;VH1-46&gt;VH1-24), and had modest mutation from germline (~5%). Ongoing epitope mapping has indicated V3 is a dominant target; however other regions including V1/V2 and C1/C5 were also targeted. The majority of the mAbs are high avidity, and a subset can mediate Ab-dependent cellular phagocytosis; additional functional analysis is ongoing. Bone marrow was evaluated ~7 months after immunization (n=3), and although ELISpot of CD138+ plasma cells could readily detect influenza specific IgG Ab secreting cells (ASCs), Env-specific IgG ASCs were not convincingly detected by ELISpot. However, when using VH deep sequencing of the bone marrow (n=4), multiple members of plasmablast-derived mAb clonal lineages were detected. Our results indicate that HIV-1 Env-specific B cells are present in human bone marrow after vaccination, but may persist at very low frequency.
Rescue of vaccine immunity with nicotine and isoproterenol after total body irradiation
Authors: Gandhi Deep , Lehtimaki Mari K. , Surujdin Ryan , Aryankalyil Joseph , McFarland Hugh I. , Rosenberg Amy S. 
Published: January 2023

Abstract
Radiation exposure results in DNA damage and apoptosis of lymphocytes, including memory T cells, leading to the loss of vaccine immunity and resulting in a potentially lethal susceptibility to infection. We have shown that memory CD8+ T cells are preserved by revaccination within 3–4 days after exposure to sub-lethal γ radiation. This study explores therapeutics selected to replicate the effects of revaccination. These therapeutics may promote memory T cell survival by acting on survival pathways stimulated by T cell activation. Using a Listeria monocytogenes (LM) model in mice, nicotine tartrate and isoproterenol were chosen from a screen of 22 therapeutic candidates. Both drugs have been shown to act on the AKT and ERK1/2 survival pathways to prevent apoptosis and promote cell survival and DNA repair. Thirty days after vaccination against LM, mice were irradiated and treated 1 day later with one of the therapeutics. Thirty days later, mice were challenged with wild-type LM, followed by harvest and plating of the spleen. Colonies were counted as a measure of vaccine immunity to LM. Nicotine significantly decreased the number of LM colonies when administered subcutaneously in a TiterMax adjuvant emulsion, as well as transdermally in the form of a patch. The decrease in LM was comparable to revaccination. Similarly, pilot experiments using isoproterenol show decreased colony counts, indicating potential preservation of vaccine immunity. Further studies will include varying doses of isoproterenol and varying routes of administration, as well as combinations of treatments. These therapeutics offer a practical effective means of preserving vaccine memory as a potential new medical countermeasure for Acute Radiation Syndrome.
Activated macrophages as pathogenesis factors in Ebola virus disease in humans
Authors: McElroy Anita K. , Shrivastava-Ranjan Punya , Harmon Jessica R. , Martines Roosecelis , Silva-Flannery Luciana , Flietstra Timothy D. , Kraft Colleen S. , Mehta Aneesh K. , Lyon G. Marshall , Varkey Jay , Ribner Bruce , Nichol Stuart T. , Zaki Sherif , Spiropoulou Christina 
Published: January 2023

Abstract
Ebola virus disease (EVD) is associated with elevated cytokine levels, that are more pronounced in fatal cases. This type of hyperinflammatory state is reminiscent of other inflammatory disorders, such as macrophage activation syndrome (MAS) or hemophagocytic lymphohistiocytosis (HLH). These are both part of a spectrum of rheumatologic phenomena characterized by both macrophage and T cell activation. These disorders can be secondary to infection, malignancy, underlying rheumatologic disorder, or, paradoxically, immune deficiency. An evaluation of two cohorts of patients with EVD revealed that several of the common laboratory features of MAS and HLH are shared by EVD. Neither fibrinogen nor soluble IL-2 receptor were significantly different between fatal and non-fatal cases. However, elevated levels of triglycerides, ferritin and sCD163, a marker of macrophage activation were noted in patients with EVD and they correlated with disease severity and a fatal outcome. Furthermore, significant immunoreactivity for CD163 + cells in host tissues was observed in fatal cases, predominantly in areas of extensive immunostaining for EBOV antigens. These data suggest that host macrophage activation contributes to EVD pathogenesis and that directed anti-inflammatory therapies could be beneficial in the treatment of EVD.
-Microglia mount a robust immune response to Rift Valley Fever virus that is dependent on MAVS and independent of TLR7
Authors: Weilhammer Dina R. , Bourguet Feliza , Rasley Amy 
Published: January 2023

Abstract
The mosquito-borne Rift Valley Fever virus (RVFV) is a category A biodefense pathogen due to the potential for intentional spread by aerosol and the lack of any licensed vaccine or antiviral therapeutics. Animal studies and limited data from human infection have demonstrated that RVFV pathogenesis following aerosol exposure differs from subcutaneous exposure, and is characterized by severe encephalitis, high viral titers in the brains, and long lasting neural pathology in human survivors of infection. Despite the brain being a major target of viral replication and tissue damage, little is known about innate immune responses to RVFV in the brain following aerosol infection. Thus, we are investigating the responses of the resident innate immune cells of the brain microglia and astrocytes to RVFV infection. Microglia mount a robust response to RVFV infection evidenced by upregulation of immunoregulatory genes, secretion of cytokines and upregulation of surface markers of activation. The response of microglia to RVFV is dependent upon MAVS and independent of TLR7, with cells derived from MAVS knockout animals unresponsive to infection while cells derived from TLR7 knock out animals responded similarly to infection as wild type cells. Experiments to determine the in vivo innate immune response to RVFV in the brain are ongoing. Understanding the in vivo innate immune response in the brain will be will be critical to the development of vaccines and antiviral therapeutics that are successful in preventing viral encephalitis caused by RVFV.
HPV18 E1-antigen specific CD8+ T cells show cross-reactivity against cells expressing E1 from HPV16, 31, 33 and 53.
Authors: Amador Alfredo , Amador Juan Carlos , Lizano Marcela 
Published: January 2023

Abstract
CD8+ mediated immune response plays a major role in the clearance of Human Papillomavirus (HPV) infected cells. Although HPV vaccines prevent HPV infections through humoral response, they do not protect against established infections and its cross protection is limited. In the HPV infection, the expression of E1 helicase during viral replication makes it a potential immunological target. The E1 protein is one of the most conserved proteins among papillomaviruses. We demonstrate in previous work, that immunization of HPV type 18 E1 protein plus α-GalactosylCeramide (α-GalCer) elicited CD8 T cell-immune response, able to eliminate tumor cells expressing HPV18 E1 protein. For this study, we analyzed the amino acids sequence of E1carboxi-terminal (CT) domains from HPV18, 16, 31, 33 and 53, using Rankpep and Clustal software to determine the number of conserved peptides among E1 proteins. These sequences share 20 predicted peptides. We cloned E1-CT domains of HPV16, 31, 33 and 53, and its expression in B16-F0 cells was determine. We show that CD8 T cells from mice immunized with HPV18 E1 protein plus α-GalCer, are actively cytotoxic in co-culture with B16-F0 cells expressing different E1-CT proteins in comparison with unimmunized mice, showing a cross-reactivity. Cytotoxicity activity was evaluated by detection of CD107a and CD107b on the CD8 T cells surface as part of cytotoxic granule exocytosis, through flow cytometry. Ongoing experiments will examine if mice immunized with HPV18 E1 protein plus α-GalCer are able to eliminate tumors cells expressing different E1-CT proteins in a mouse model. The characterization of new immunological targets against HPV, could help to develop new strategies to clearance HPV established infections.