bluuebunny/crossref_metadata_2025_split huggingface dataset:
Gender and alcohol differentially influence DC signaling and ability to initiate an anti-tumor immune response. (TUM10P.1026)
Authors: Watkins Stephanie , Thompson Matthew 
Published: January 2023

Abstract
Gender disparity and effect of alcohol has been observed in cancer in relation to incidence, disease aggressiveness and prognosis. However, the role of the immune system and the activation of an anti-tumor immune response based on these parameters are unclear. Ethanol is known to reduce the DC’s ability to present antigen in the setting of an infection, but the signaling mechanisms effected to regulate DC functions which maybe critical in cancer are unclear. Some of the most successful cancer therapies to date have focused on hormone receptor blockade in tumor cells. Hormones, including androgen and estradiol, can dampen immune responses, but immune suppression or activation has not been studied during hormone deprivation therapy or upon previous exposure to alcohol. Tumor-associated dendritic cells (TADC) are key regulators of cytotoxic T-cell (CTL) function and may serve as a critical target for immunotherapy. Therefore, in the current study, we sought to determine the effect of alcohol on hormone receptor signaling, androgen receptor (AR) and estrogen receptor (ER), in TADC. The changes in regulation of these signaling pathways have a critical impact on the transcriptional and translational regulation of factors known to induce immune suppression and may be a key factor to consider when designing immune therapies for cancer.
Simulation of B cell affinity maturation explains enhanced antibody cross-reactivity induced by the polyvalent malaria vaccine AMA1 (VAC11P.1063)
Authors: Chaudhury Sidhartha , Wallqvist Anders , Reifman Jaques 
Published: January 2023

Abstract
Polyvalent vaccines use a mixture of antigens representing distinct pathogen strains in order to induce a broadly reactive immune response. However, it is unclear how polyvalency alters the fine specificity of the antibody response and what those consequences might be for protection. Here, we present a coarse-grain model of B cell affinity maturation during monovalent and polyvalent vaccinations that predicts the fine specificity and cross-reactivity of the antibody response. We stochastically simulate affinity maturation using a population dynamics approach where the host B cell repertoire is represented explicitly, and individual B cell sub-populations undergo rounds of stimulation, mutation, and differentiation. Antigens contain multiple epitopes and are present in subpopulations of distinct pathogen strains. This epitope and strain-specific model enables us to simulate the polyclonal response in granular detail and identify immune mechanisms driving serum specificity and cross-reactivity. We applied this approach to study the antibody response to a polyvalent vaccine based on the polymorphic malaria antigen AMA1. Our simulations show that polyvalent AMA1 vaccination induces an enhanced cross-reactive antibody response, primarily through a shift in affinity maturation that favors B cells specific to shared and cross-reactive epitopes, and demonstrates how a polyvalent vaccine with a small number of strains and only moderate allelic coverage may be broadly neutralizing.
Flagellin’s hypervariable D2/D3 domain is required for robust anti-flagellin primary antibody responses (VAC11P.1065)
Authors: Smith Kelly , Lopez-Yglesias Americo , Lu Chunchi , Zhao Xiaodan , Strong Roland 
Published: January 2023

Abstract
Bacterial flagellin is a well-known agonist of the innate immune system. Several clinical trials investigating flagellin fusion proteins have demonstrated promising results for inducing protective immunity towards influenza virus, which has been largely attributed to flagellin activation of TLR5. Our lab recently demonstrated that the Salmonella enterica serovar Typhimurium flagellin protein, FliC, induces antibody responses in mice through a third pathway that is independent of TLR5, Casp1, and MyD88. Herein, we define the structural features of FliC that contribute to this third pathway. By destroying the Naip5/6 (D0 domain) or TLR5 (D1 domain) recognition sites, we demonstrate that neither affected the TLR5-, inflammasome- and MyD88-independent antibody responses towards FliC. In contrast, deletion of the D2/D3 domain eliminated primary anti-flagellin antibody responses. Optimal primary and secondary anti-flagellin antibody responses required TLR5- and inflammasome-mediated recognition, and FliC’s D2/D3 domain. We demonstrate FliC’s D2/D3 domain is required for induction of primary antibody responses and robust secondary antibody responses. Our results indicate that FliC’s D2/D3 domain is essential for flagellin’s robust immunogenicity and suggest that the D2/D3 domain interacts with the host immune system to augment antibody production. Thus, the D2/D3 domain of FliC may also be critical for optimal immunogenicity and antibody responses in flagellin based vaccines.
Simulation explains the effect of preexisting memory on variable immune responses to 2009 pH1N1 influenza vaccination (VAC11P.1067)
Authors: Anderson Christopher , Topham David 
Published: January 2023

Abstract
Although it is generally assumed older individuals respond poorly to vaccination, the pandemic 2009 H1N1 vaccine demonstrated that this is not always true. Interestingly, there is considerable antigenic likeness between the pandemic 2009 H1N1 virus and the H1N1 viruses that circulated between 1918-1957. During the 2009 H1N1 pandemic the majority of individuals vaccinated with 2009 H1N1 mounted an immune response to the conserved stalk region of the influenza hemagglutinin. Older individuals alive during 1918-1957, however, mounted a response primarily to the variable head region of hemagglutinin. Memory B cells seem to play the dominant role in both of these responses. A proposed explanation for this difference is that older individuals were exposed to 1918-like viruses and contained preexisting memory B cells capable of cross-reacting with the 2009 H1N1 head epitopes. To test this hypothesis, we have developed a course-grain theoretical model using the theory of Shape Space to simulate the human humoral response. By simulating the variant influenza strains each age group would be exposed to over their lifetime, we can directly test the effect of exposure to 1918-like viruses on the response to pandemic 2009 H1N1. Understanding how differences in exposure history influence the B cell memory repertoire is crucial to predicting how individuals will respond to the future influenza vaccines.
PD-1 expression on peripheral blood lymphocytes enables direct enrichment of mutation-specific lymphocytes (VAC12P.1117)
Authors: Gros Alena , Tran Eric , Pasetto Anna , Parkhurst Maria R , Prickett Todd , Gartner Jared , Yu Zhiya , Wunderlich John , Robbins Paul , Yang James , Rosenberg Steve 
Published: January 2023

Abstract
Identification and isolation of mutation-specific T-cells is a major obstacle to the development of effective cancer immunotherapies. The tumor is a natural sink for neo-antigen specific cells, but these are far less frequent in peripheral blood, a more accessible and abundant source of T cells. Previous studies have revealed that PD-1 expression in the tumor microenvironment can identify the patient-specific repertoire of tumor and mutation-specific cells infiltrating human tumors. Here, we evaluated the potential utility of PD-1 expression on circulating lymphocytes to identify and enrich for mutation-specific cells. Selection of CD8+PD-1+ lymphocytes circulating in peripheral blood, but not the bulk or CD8+PD-1- cells, led to the direct enrichment of mutation-specific cells in three melanoma samples tested, with at least 1, 3 and 5 unique patient-specific neo-antigens recognized, respectively. The PD-1+ derived cells also displayed autologous tumor recognition. Furthermore, CD8+PD-1+ and PD-1hi cells isolated and expanded from the blood from a patient with colorectal cancer led to the identification of mutation-specific cells targeting two tumor neo-antigens. These findings provide a novel strategy to harness naturally-occuring mutation-specific T cells present in peripheral blood for the development of personalized T -cell based therapies to treat cancer.
B7-H1/PD-1 signals in carcinoma and lymphoma immunopathogenesis and immunotherapy (VAC12P.1118)
Authors: Clark Curtis , Liu Yang , Murthy Kruthi , Sareddy Gangadhara , Vadlamudi Ratna , Hurez Vincent , Curiel Tyler 
Published: January 2023

Abstract
αB7-H1 (αPD-L1) reportedly treats cancer by blocking PD-1 signals, but few formal data are reported. We showed B16 melanoma is CD80-PD-1-B7-H1+. αB7-H1 slowed subcutaneous (SQ) B16 in wild type (WT), B7-H1 KO and CD80 KO, with little difference between groups. αB7-H1 did not slow B16/B7-H1lo tumors in B7-H1 KO mice, formally showing tumor B7-H1 mediates αB7-H1 effects. αPD-1 slowed B16 in WT or B7-H1 KO, but not B16/B7-H1lo in B7-H1 KO, formally showing B7-H1/PD-1 effects in αB7-H1. Tumor B7-H1 variably predicts αB7-H1 efficacy, possibly due to variable tumor B7-H1 expression. To model variable B7-H1, we gave B16 or B16/B7-H1lo on both flanks, or each on opposite flanks of the same WT mice. αB7-H1 slowed B16, but not B16/B7-H1lo, unless B16 was on the other flank, suggesting spread of anti-tumor immunity, helping explain variable αB7-H1 effects by tumor B7-H1 status. We found EL4 T cell lymphoma is CD80loB7-H1loPD-1hi. αB7-H1 and αPD-1 did not slow SQ EL4. Unexpectedly, EL4/B7-H1hi exhibited significant growth delay after SQ or intravenous challenge in WT. EL4/B7-H1hi grew well in vitro, but in clusters as opposed to EL4. αPD-1 or αB7-H1 in vitro blocked clusters but such pre-treated cells still grew slowly in vivo suggesting negative inter-cell B7-H1/PD-1 signals. Our data formally show B7-H1/PD-1 signals in αB7-H1 treatment effects, help explain variable αB7-H1 effects by tumor B7-H1 status, and suggest novel and specific effects in T cell lymphomas requiring more study.
One-shot sustained release nanoparticle vaccines (VAC13P.1133)
Authors: Hook Sarah , Bobbala Sharan , Mitra Ashim 
Published: January 2023

Abstract
Sustained release of vaccines over an extended period of time may reduce or negate the need for multiple vaccinations (boosters) and also effectively enhance the immunogenicity of subunit vaccines. We have investigated the physcial, chemical and immunological properties of polymeric thermogelling formulations loaded with nanoparticulate protein and peptide based vaccines. The formulations were developed to be free-flowing liquids at room temperature and to form stable gels at body temperature. The vaccine components were loaded into nanoparticles before incorporation into the polymers in order to achieve synchronous release of antigen and adjuvant. The ability of the vaccines to stimulate long lived cellular and humoral responses after a single dose of antigen was investigated in mice. A single dose of formulations could induce detectable responses 50 days post immunisation and could protect mice in a tumor challenge model.
Use of a cytotoxic peptide as an immunotherapeutic agent in the treatment of metastatic breast cancer (VAC13P.1134)
Authors: Khaled Annette , Bassiouni Rania , Limaye Arati , Oyer Jeremiah , Igarashi Robert , Flores Orielyz , Perez J. , Copik Alicja 
Published: January 2023

Abstract
Breast cancer is a challenge for immunotherapy because of its genetic heterogeneity and decreased immunogenicity, which impedes the use of immune checkpoint blockade. A promising approach is to generate dying cancer cells that operate like a vaccine to induce a tumor-specific immune response and eradicate residual cancer cells. This is termed immunogenic cell death (ICD) and is characterized by a unique molecular signature that stimulates immunity. To develop a novel ICD agent for cancer immunotherapy, our group discovered a therapeutic peptide, CT20p, and a nanotechnology-based platform to concentrate CT20p in breast tumors. Treatment of mice with nanomolar amounts of CT20p caused tumor regression, and dying breast cancer cells expressed markers characteristic of ICD: calreticulin (Crt) and heat shock protein (HSP)-70. The intracellular target of CT20p is a protein called chaperonin-containing T-complex (CCT) that folds actin and tubulin. CCT was overexpressed in breast cancer cells susceptible to CT20p. In contrast, normal epithelial cells, macrophages or NK cells, which have low levels of CCT, were unaffected by CT20p. Breast cancer cells treated with CT20p displayed alterations in IRE1 and PERK, mediators of the unfolded protein response (UPR) that are upstream drivers of ICD signals. Hence, CT20p-treated breast cancer cells were more effectively killed by NK cells and ingested by phagocytes, demonstrating that CT20p is a robust stimulator of innate immunity.
HPV specific immunotherapy for cervical intraepithelial neoplasia using VGX-3100 induces regression of cervical lesions and potent T cell responses: results from a randomized, double-blind, placebo-controlled phase II study (VAC13P.1135)
Authors: Morrow Matthew , Trimble Cornelia , Shen Xuefei , Dallas Michael , Weiner David , Boyer Jean , Yan Jian , Kraynyak Kimberly , Sylvester Albert , Giffear Mary , Marcozzi-Pierce Kathleen , Shah Divya , Broderick Kate , Khan Amir , Lee Jessica , Humeau Laurent , Sardesai Niranjan , Bagarazzi Mark 
Published: January 2023

Abstract
Here we report the results of a Phase II study assessing the safety and efficacy of VGX-3100 in 167 women with biopsy-proven CIN 2/3 with concurrent HPV16/18 infection. The randomized, placebo-controlled, double-blind study evaluated cervical tissue changes after three 6 mg intramuscular doses of VGX-3100 followed by electroporation (EP) with Inovio’s CELLECTRA®2000 device at weeks 0, 4, and 12. Cervical tissue was examined before treatment and 9 months later. The study met its primary efficacy endpoint; the percentage of patients who had regression of CIN 2/3 to CIN 1 or no disease at 6 months post third dose was significantly higher in the VGX-3100 group compared to the placebo group (p=0.017). In addition, the trial demonstrated the ability of VGX-3100 clear HPV infection concurrent with regression of CIN lesions. The study also explored humoral and cellular immune responses to VGX-3100 in blood samples taken periodically during the trial. ELISA as well as IFN-g ELISpot results revealed significantly higher responses in the VGX-3100 treated group than in the placebo group, suggesting that VGX-3100 was able to robustly engage the patients’ immune system. Altogether, the successful phase 2 results represent a significant milestone in the development of active immunotherapies not only to robustly engage the immune system but also to treat cancer and infectious diseases and have the potential to provide physicians an important alternative to surgery to treat CIN 2/3 disease.
mRNA loaded CMRF-56+ dendritic cells: a novel anti-cancer vaccination strategy (VAC13P.1122)
Authors: Papadimitrious Michael , Anguille Sebastien , Bryant Christian , Kupresanin Fiona , Verma Nirupama , Lo Kevin , Clark Georgina , Newman Elizabeth , Bradstock Kenneth , Berneman Zwi , Fromm Phillip , Hart Derek 
Published: January 2023

Abstract
Current dendritic cell therapeutic vaccinations using tumour associated antigen (TAA) loaded monocyte derived dendritic cells (MoDC) has demonstrated anti-cancer immune responses. However, functional and transcriptional differences between blood dendritic cells (BDC) and MoDC have emerged. Using the GMP human CMRF-56 IgG4 chimeric monoclonal antibody, we are able to obtain clinical-grade BDC appropriate for loading TAA mRNA. We evaluated hCMRF-56 as an improved clinical preparation for BDC immune therapy by 1) their ability to initiate anti-tumour antigen immune response following loading of TAA mRNA 2) comparing CMRF-56+ BDC and MoDC capacity to migrate to draining lymph nodes in a preclinical xenograft model. Characterisation of the proposed clinical formulation identified up-regulation of CD40 and CD80 post GM-CSF activation and GM-CSF activation with mRNA nucleofection, respectively. Nucleofected CMRF-56+ BDC migrated towards CCL21 in vitro. CMRF-56+ BDC and MoDC were administered to SCID mice to monitor their in vivo migration to inguinal lymph nodes. Flu Matrix Protein 1 IFNγ responses were observed by CD4+ and CD8+ lymphocytes. Stimulation of CMRF-56+ BDC loaded with Wilms Tumor 1 antigen mRNA was able to induce CD4+ and CD8+ T cell responses. Our data suggests BDC can be effectively nucleofected with TAA mRNA. This demonstrates the efficacy of mRNA nucleofected BDC to warrant further clinical investigation
Pro-inflammatory cytokine production by activated monocytes and macrophages in response to cowpox virus infection in cynomologus macaques (VIR9P.1144)
Authors: Janosko Krisztina , Cohen Melanie , Josleyn Nicole , Zhang Tengfei , Cong Yu , Jahrling Peter , Johnson Reed 
Published: January 2023

Abstract
Monocytes and macrophages play pivotal roles in host defense against microbial and viral pathogens through production of inflammatory and cytotoxic mediators, phagocytic activity, and activation of T cells. In previous studies, we reported significant expansion of CD14+ cells following intravenous cowpox virus Brighton Red (CPXV) infection of cynomologus macaques accompanied by increased levels of pro-inflammatory cytokines in plasma. Here, monocytes were assayed for production of pro-inflammatory cytokines and chemotactic factors during CPXV disease progression at days 3, 4, 6, and 7 post-infection in a serial sacrifice study of cynomologus macaques intravenously inoculated with 5 x 106 PFU CPXV. We measured monocyte absolute cell numbers in blood, frequencies of monocytes and macrophages in blood, and compared normal and infected monocytes through production of pro-inflammatory cytokines IL-6, IL-8, MCP-1, and IFNγ. Our results demonstrated an early increase in frequency and absolute numbers of total monocytes in blood with a rapid decline in moribund animals. Cytokine and chemokine analysis demonstrated an increase in IL-8 and MCP-1 expression over the course of disease but little IFNγ or IL-6. Pox antigen positive monocytes also expressed IL-8, but were not observed to express MCP-1. This suggests pox infection may alter cytokine production profiles of monocytes and may play a role in disease progression.
Role of IFN-α signaling in T cell pool dysregulation during chronic exposure to type-I IFN under lymphopenic conditions: impact on HIV pathogenesis (VIR9P.1145)
Authors: Le Saout Cecile , Hasley Rebecca , Imamichi Hiromi , Tcheung Lueng , Hu Zonghui , Smith Mindy , Rupert Adam , Sneller Michael , Lane H. , Catalfamo Marta 
Published: January 2023

Abstract
HIV infection and its associated chronic immune activation alter T cell homeostasis leading to CD4 T cell depletion and CD8 T cell expansion. The mechanisms behind these outcomes are not totally defined and only partially explained by the direct cytopathic effect of the virus. We established a murine model of immunpoathogenesis in which adoptive T cell transfer into lymphopenic hosts chronically treated with IFN-α leads to CD4 T cell depletion and CD8 T cell expansion, recapitulating the alteration of the T cell pools observed in HIV infected patients. In these conditions, CD4 T cells undergoing IL-7/lymphopenia induced-proliferation upregulate their level of the Signal Transducer and Activator of Transcription 1 (STAT1) resulting in enhanced CD4 T cell responsiveness to IFN-α. In this setting, CD4 T cell depletion resulted from an indirect effect of IFN-α driven inflammatory environment, since animals with IFNAR deficient T cells underwent the same degree of CD4 T cell depletion than wild type animals. In contrast, direct IFN-α signaling through IFNAR on CD8 T cells was necessary for their expansion induced by chronic exposure to Type-I IFN under lymphopenic conditions. These findings suggest that direct and indirect effects of IFN-α signaling may play a role in the pathogenesis of HIV infection. Further analysis of this pathway may contribute to the development of new strategies to reverse the dysregulation of the T cell pools seen in patients with HIV infection.
Using gel centrifugation to determine the monomer-dimer equilibrium of the HIV-1 5’-leader (VIR9P.1162)
Authors: Bolden Nicholas , Van Verna , Swanson Canessa , Monti Sarah , Summers Michael 
Published: January 2023

Abstract
An estimated 35 million people live with Human Immunodeficiency Virus (HIV-1), with approximately 1.7 million associated deaths per year. HIV-1 is a retrovirus that infects the T cells of the host’s immune system. After infection, the virus reverse-transcribes its RNA genome into DNA and integrates the viral DNA into the host DNA, which is eventually transcribed into RNA by the host cell. The 5’ untranslated region (UTR) of the RNA, is the most conserved region of the genome. It exists in equilibrium between a monomeric form, important for translation, and a dimeric form, important for genome packaging. While gel electrophoresis is usually used to determine the equilibrium of monomer and dimer, we have developed a new technique that uses gel centrifugation. We are developing this technique as it may allow us to look at the monomer-dimer equilibria of different RNAs, such as HIV-2, which have weaker “kissing” dimer interactions. When gel electrophoresis is used on these dimers, the magnesium that stabilizes the dimer is drawn towards the opposite pole as the RNA, providing inaccurate data by dissociating the dimers and causing more monomer to be visualized. Magnesium containing gels are used to combat this, but it is difficult to determine how much magnesium is needed to obtain accurate results. Future work includes testing this method on retroviruses with a “kissing dimer” interaction and eventually determining a way to quantify the amount of monomer and dimer present.
Mechanisms of regulatory T cell activation and expansion utilizing virus-specific CD8+ T cells (VIR10P.1172)
Authors: Myers Lara , Joedicke Jara , Carmody Aaron , Messer Ron , Dittmer Ulf , Kim Hasenkrug 
Published: January 2023

Abstract
The CD8+ T cell response to acute Friend virus (FV) infection is critical for recovery from lethal disease. However, in the late acute phase of infection this response becomes suppressed by regulatory T cells (Tregs), thereby leading to chronic infection. A major question regarding these events is how does FV infection induce the Treg response. We discovered a novel subset of natural Tregs that expand disproportionately in response to FV infection. These Tregs bear Vβ5+ T cell receptors, which are unique because of their known specificity for a superantigen (Sag) encoded by an endogenous retrovirus. Our results demonstrate that these Sag-reactive Tregs are independent of IL-2 but dependent on TNFα. Studies revealed that the expansion of these Tregs is actually driven the CD8+ T cell response. Activated, FV-specific CD8+ T cells upregulate membrane bound TNFα, which induces Vβ5+ Treg expansion by binding to TNFR2 receptors on the Tregs. Thus the expansion of the Vβ5+ Tregs is dependent on activated CD8+ T cells, the eventual targets of Treg-mediated suppression. These results demonstrate a new pathway of Treg expansion and two-way intercellular communication between Tregs and activated CD8+ T cells. Control by Tregs appears to be a natural mechanism to prevent immunopathological damage from CD8+ T cell responses that are too vigorous or too sustained. Modulation of this Treg subset has implications not only for the treatment of viral infections but also autoimmune diseases.