bluuebunny/crossref_metadata_2025_split huggingface dataset:
Overexpression of LLT1 (CLEC2D) on prostate cancer cells inhibits NK cell-mediated killing through LLT1-NKRP1A interaction (TUM10P.1052)
Authors: Mathew Stephen , Mathew Porunelloor 
Published: January 2023

Abstract
Prostate cancer is the most common type of cancer diagnosed and the second leading cause of cancer-related death in American men. Natural Killer (NK) cells are the first line of defense against cancer and infections. In order to establish and grow, cancer cells must escape NK cell-mediated killing. NK cell function is regulated by a delicate balance between signals received through activating and inhibitory receptors. We have identified LLT1 (Lectin-like transcript 1 or CLEC2D) as a counter-receptor for the NK cell inhibitory receptor NKRP1A (CD161). Interaction of LLT1 expressed on target cells with NKRP1A inhibits NK cell activation. Recently, we have found that LLT1 is overexpressed on DU145, LNCaP, and PC3 prostate cancer cells both at the mRNA and protein level. Blocking LLT1 interaction with NKRP1A by anti-LLT1 mAb increased the killing of prostate cancer cells. NK-mediated killing of DU145 in the presence of anti-LLT1 mAb showed the maximum killing. Also, LLT1 was found to be overexpressed in primary prostate cancer tissues, whereas its level of expression was minimal in normal prostate tissue. The results indicate that prostate cancer cells may evade immune attack by NK cells by expressing LLT1 gene to inhibit NK cell-mediated cytolytic activity through LLT1-NKRP1A interaction. Blocking LLT1-NKRP1A interaction will make prostate cancer cells susceptible to killing by NK cells and therefore may be a new therapeutic option for treatment of prostate cancer.
Development of humanized mouse models to study human immune system-tumor interactions (TUM10P.1055)
Authors: Aryee Ken-Edwin , Shultz Leonard , Greiner Dale , Brehm Michael , Jurczyk Agata 
Published: January 2023

Abstract
Cancer progression involves interplay between tumor cells and non-malignant stoma, including immune cells. Our understanding of the interactions between immune systems and tumors is based mostly on mouse models. However many differences exist between murine and human biology, and translation of findings from mice to clinical application is challenging. The study of human immune systems and tumors is limited by logistical and ethical restrictions of working with primary specimens from patients. Here we describe a humanized mouse model to study the in vivo interactions between human immune systems and human tumors. In these studies NOD-scid IL2rgnull (NSG) mice expressing human SCF, GM-CSF and IL-3 (NSG-SGM3) were engrafted with human fetal thymus and fetal liver-derived hematopoietic stem cells (BLT). NSG-SGM3-BLT mice support high levels of human cell chimerism, including development of human myeloid cells, T cells and B cells. Engrafted NSG-SGM3-BLT mice were implanted with patient melanoma cells and monitored for tumor growth and immune system homeostasis. The human melanoma grew with similar kinetics in NSG-SGM3-BLT mice as compared to control NSG-SGM3 mice. Human immune cells, including human macrophage and T cells, infiltrated the melanoma. The T cell infiltrate was dominated by human FOXP3+ Treg and by PD1+ CD4 and CD8 T cells. These data show that NSG-SGM3-BLT mice, are a promising model to study human immune system-tumor interactions and to test novel therapies.
Exercise reduces tumorigenesis in a K-ras mouse model of non-small cell lung cancer (TUM10P.1057)
Authors: Lowder Thomas , Abadi Parisa , Bernardo Jenina , Pulicken Catherine 
Published: January 2023

Abstract
Exercise has been shown to reduce the prevalence of certain cancer subtypes, prolong survival rates, and improve quality of life of cancer patients. Exercise’s role in cancer includes not only prevention and post-treatment care, but also the reduction in cancer progression. Moderate-intensity exercise has been shown to have significant inhibitory effects on tumor initiating mechanisms in mice resulting in decreased tumor incidence for a variety of cancers including pancreatic, gastrointestinal, and mammary. This is the first report of the role that exercise plays in the suppression of spontaneous murine lung cancer. Sedentary mice (N = 14) lung tumor count was 40.57 ± 3.483 tumors (mean ± SEM). Lung tumor count in the exercised mice (N = 10) was significantly reduced to 21.80 ± 1.705 tumors (p &lt; 0.001). Sedentary mice (N = 6) tumor percentage of lung volume was 12.34 ± 0.528%. Percent lung tumor volume in exercised mice (N = 8) was significantly reduced to 6.913 ± 0.262% resulting in a 44% reduction of tumors within lung tissue. IL-6 and TNF-alpha spleen data did not show any significant changes due to exercise in relation to lung cancer. These results demonstrate that moderate exercise can slow the progression of tumorigenesis in a mouse model of lung cancer.
IL-36 is required for the induction of therapeutic immunity by Tbet gene-modified dendritic cells. (TUM10P.1024)
Authors: Weinstein Aliyah , Chen Lu , Storkus Walter 
Published: January 2023

Abstract
Our lab has developed a dendritic cell (DC) vaccine as a means of overcoming immune dysfunction in the tumor microenvironment (TME) and generating a therapeutic anti-tumor immune response. As protective Type 1 immune responses are characterized by intrinsic expression of the Tbet transactivator in T cells and DC, we engineered DC with Tbet cDNA (ie, DC.Tbet) and injected these cells into the TME of syngeneic tumor-bearing mice as a therapy. Treatment of MCA205 sarcomas with DC.Tbet promoted the rapid (hours) and sustained (days-weeks) infiltration of Type 1-polarized CD4+ and CD8+ TIL into the TME and led to increased TME expression of factors characteristic of ectopic lymphoid structures (ELS), such as TNFSF14, CCL19, and CCL21. DC.Tbet cells revealed a 60-fold increase in the level of IL-36gamma mRNA over mock-transduced DC and inhibition of signaling through the IL-36 receptor (IL-36R) using natural antagonist IL-1F5 abrogated the ability of DC.Tbet therapy to inhibit tumor growth in vivo, concurrent with reduced recruitment of therapy-induced CD4+ and CD8+ TIL. The efficacy of DC.Tbet therapy was similarly negated in MCA205-bearing IL-36R-/- hosts. These data suggest a mechanism whereby treatment with DC.Tbet leads to recruitment of anti-tumor TIL via an IL-36R signaling-dependent mechanism that supports the development of ELS in the TME. These findings foreshadow the clinical use of IL-36gamma in cancer vaccine formulations as a means to promote therapeutic immunity.
Human antibody specificities that confer protective immunity to poxvirus infections (VAC11P.1109)
Authors: Gilchuk Iuliia , Gilchuk Pavlo , Hammarlund Erika , Slifka Mark , Lampley Rebecca , Sapparapu Gopal , Eisenberg Roselyn , Cohen Gary , Xiang Yan , Joyce Sebastian , Crowe James 
Published: January 2023

Abstract
Immunization with vaccinia virus (VACV) induces cross-protective immunity to variola, the causative agent of smallpox, and other clinically important poxviral species, such as cowpox and monkeypox viruses. Vaccine-mediated protection has been correlated with elicitation of broad neutralizing antibodies (Abs). However, the specificity and breadth of protective human Abs to poxviruses are largely unknown. We used a highly-optimized human hybridoma technology to generate a panel of 90 anti-VACV monoclonal Abs from vaccinia-immunized subjects or from subjects who had a history of naturally-acquired monkeypox infection. Then, we assessed the neutralizing and protective capabilities of the Abs in vitro and in a lethal respiratory VACV challenge in a mouse model. A large fraction of Abs from the panel (&gt;40%) possessed neutralizing activity against VACV, cowpox and/or monkeypox viruses. Antibodies to a variety of envelope proteins in VACV extracellular virions (A33, B5) or mature virions (L1, A27, D8, H3) contributed substantially to neutralizing activity in vitro. For protective immunity in vivo, L1, A27, A33 and B5 antibodies conferred levels of protection that were comparable to those induced by live viral vaccination, especially when used in combination. Such antibody cocktails have promise for use in as immunotherapeutics in humans.
B cell memory but not antibody response is maintained in the elderly after repeated influenza vaccine immunizations and aged murine plasma cell generation is defective (VAC11P.1066)
Authors: Blomberg Bonnie , Diaz Alain , Romero Maria , Landin Ana Marie , Frasca Daniela 
Published: January 2023

Abstract
The success of a vaccine depends on both plasma cells and memory B cells. We previously showed that serum antibodies and the in vitro AID response to a new influenza vaccine are decreased in elderly individuals. We hypothesized that even though AID is decreased in the elderly, the ability to generate memory B cells might be improved by a repeated vaccine. To test this hypothesis, we recruited young and elderly individuals who had been immunized in at least two consecutive influenza vaccine seasons in which the H1N1 strain was the same. Results showed that frequencies of influenza vaccine-specific memory B cells were similar in young and elderly individuals but the levels of serum antibodies were lower in the elderly. These findings suggest that multiple re-exposures to the vaccine cause a divergence between memory B cell frequencies and antibody levels with age, which could be due to impaired memory B cell to plasma cell differentiation in the elderly. To test the hypothesis of defective plasma cell development in old mice, we measured the percentage of plasma cells and Blimp-1 in LPS-stimulated B cells and found them significantly lower in old than in young cultures. The average fold reduction in the secreted amount of IgM and IgG3 in aged cultures compared to young cultures is higher than the average reduction in CD138+ plasma cells (10-fold vs 2-fold) suggesting qualitative as well as quantitative plasma cell defects with age.
In MCA-induced sarcoma models, booster vaccination with GM-CSF-secreting whole-cell tumor vaccines maintain or improve efficacy but may alter trafficking of tumor-specific T cells (VAC13P.1128)
Authors: Messenheimer David , Jensen Shawn , Fox Bernard 
Published: January 2023

Abstract
Previously, we reported that while a single vaccination effectively generated therapeutic tumor-specific T cells for adoptive immunotherapy (AIT), repeated vaccination with the poorly immunogenic B16BL6 melanoma, modified to secrete GM-CSF, induced high levels of CD4+FoxP3+ T regulatory (Treg) cells and AIT with spleen cells was non-therapeutic. The effect could be overcome by transient depletion of CD4+ T cells, confirming the effect of Treg cells. Here experiments were performed to test whether this suppressive effect was observed in active-specific protection in 2 sarcoma models, MCA-304 and MCA-310. Mice were vaccinated once or thrice with either irradiated parental sarcoma or that sarcoma expressing GM-CSF. We did not observe significant changes in percentage or total count of splenic Treg cells under any conditions, however, tumor-specific IFN-γ release decreased in mice thrice vaccinated with GM-CSF-secreting tumors compared to parental (p &lt; 0.001). Importantly, multiple vaccination offered tumor protection that was as good or better than single vaccination. In the most strongly immunogenic tumor, MCA-304, both single and triple vaccination with parental or GM-CSF-secreting tumors provided 100% protection. However, in the weakly immunogenic, MCA-310 sarcoma, multiple vaccinations improved effectiveness with the greatest effect seen with the GM-CSF-secreting MCA-310. Our results provide a rationale for the continued use of GM-CSF as a cancer vaccine adjuvant.
G-CSF induced neutrophil invasion of the CNS is inhibited by Interferon γ (VIR9P.1150)
Authors: Chandran Ramakrishna , Cantin Edourad 
Published: January 2023

Abstract
Inflammation of the brainstem (BS) of wildtype (wt) 129 mice due to uncontrolled invasion by Ly6Chigh inflammatory monocytes (IM) and neutrophils is causally implicated in fatal HSV induced encephalitis (HSE). Anti-viral treatment with acyclovir following virus entry into BS cannot protect mice, as inflammation continues unabated. We showed previously that IL-10 regulates IM infiltration into BS. We determined the role of IFNγ, a key pleiotropic cytokine that directs the host immune response by inducing potent inflammatory or regulatory activities, in HSE. IFNγ knockout (GKO) mice developed HSE much quicker than wt or Rag mice. Surprisingly, mortality did not correlate with the ability to control virus replication but rather with massive expansion and infiltration of neutrophils into the BS. Neutrophil expansion in the absence of IFNγ was not due to increased IL-17 but rather to augmented secretion of G-CSF especially in CNS. Depletion of G-CSF by administration of anti G-CSF Ab or 25 mg IVIG (high dose), which contains anti G-CSF Ab, but not 4 mg (low dose) inhibited progenitor proliferation and neutrophil output from bone marrow and protected GKO mice. Importantly, reduction of serum G-CSF levels resulted in renewed IL-10 secretion by ICOS+ CD4 T cells and Tregs, which limited IM expansion. This study reveals that the complex interplay of IFNγ with G-CSF and IL-10 determines the ability to skew neutrophil or monocyte output from the bone marrow in response to infection.
Hepatic retinoic acid regulates group 3 innate lymphoid cells and modulates viral hepatitis (VIR9P.1151)
Authors: Sun Jiaren , Liang Yuejin , Jie Zuliang , Zhang Kangling 
Published: January 2023

Abstract
IL-22 is important for hepatoprotection in hepatitis; however, the source and regulation of this cytokine in the liver microenvironment are not well defined. Here, we present evidence for a significant expansion of IL-22+ intrahepatic cells in mice during adenovirus and LCMV infection. In addition to gamma/delta and double-negative T cell, a subset of IL-22+ cells belong to group 3 innate lymphoid cells (ILC3s). These cells contributed significantly to the establishment of the early cytokine milieu in virus-infected liver. Interestingly, retinoic acid, a metabolite of vitamin A, increased in the liver following viral infection. Moreover, retinoic acid administration promoted IL-22 production by ILC3s and protected liver from inflammatory response-related injuries. Retinoic acid inhibited Th1/CTL responses through down-regulating DC activation and T cell priming in vitro and in vivo. Mass spectrometric studies suggested that retinoic acid induced arginase 1 expression of DC and dampened its function. Lastly, hepatic IL-7 was important for ILC3-derived IL-22 production. Blockade of IL-7Ra in vivo significantly decreased IL-22 levels and exacerbated hepatic inflammation. Collectively, this study has demonstrated the importance of a unique intrahepatic subpopulation ILC3 and its cytokine production during the initial stages of viral infection in the liver.
STING-dependent sensing of polyomavirus infection (VIR9P.1158)
Authors: Shwetank .. , Barber Glen , Lukacher Aron 
Published: January 2023

Abstract
Polyomaviruses (PyV) are nonenveloped DNA viruses that persist as low-level asymptomatic infections in a variety of vertebrates, including humans. In immunosuppressed individuals, the human BK and JC PyVs may cause transplant-associated nephropathy and progressive multifocal leukoencephalopathy, respectively. Mouse polyomavirus (MPyV) allows investigation of PyV immunity in a natural host. After caveolae-/clathrin-mediated endocytosis, PyV virions traffic in microtubule-guided microvesicles from endosomes to the ER, where uncoating is initiated. Unknown is whether complete uncoating occurs in the cytosol, exposing the viral DNA to cytosolic DNA sensors, before it is transported to the nucleus where viral replication and assembly occur. Here, we report that persistent MPyV infection in mice is associated with chronically elevated IFN-β transcripts, and that WT primary mouse embryo fibroblasts (MEFs) infected with MPyV upregulate IFN-β, TNF-α and ISG (PKR and MDA-5) mRNAs. However, MPyV infection failed to induce expression for these transcripts in MEFs from STING-/- mice. Interestingly, MPyV acute infection activated NK cells in WT, but not in IFNαβR-/- mice or in STING-deficient (Goldenticket) mice. Together, these data suggest that MPyV-induced activation of NK cells requires Type I IFN and a STING-dependent cytosolic DNA sensing pathway(s). Moreover, these data provide strong evidence that PyV DNA is exposed in the cytosol and activate innate immune sensors.
HIV elite controllers have lower frequencies of CD14dimCD16+ inflammatory monocytes with greater CX3CR1-dependent tissue homing potential than viremic controllers (VIR9P.1138)
Authors: Palmer Christine , Romero-Tejeda Marisol , Scully Eileen , Jost Stephanie , Seaman Michael , Goldenthal Ariel , Piechocka-Trocha Alicja , Pereyra Florencia , Walker Bruce 
Published: January 2023

Abstract
Without antiretroviral therapy, a small fraction of HIV-infected patients does not progress to AIDS. Such elite controllers (EC) or viremic controllers (VC) maintain undetectable or low levels of viremia, respectively. Generation of broadly neutralizing antibodies (bNAb) does not correlate with viral control, but might enhance antibody-dependent cellular phagocytosis by monocytes. Monocytes are classified into CD14+CD16-, CD14+CD16+ and CD14dimCD16+ monocytes. The latter show increased inflammatory responsiveness and are elevated during chronic HIV-1 infection. We measured markers of T cell activation and monocyte subset distribution and quantity, and investigated the relationship between these parameters and production of bNAb to identify markers for the development of bNAbs. We showed that VC display increased frequencies of CD38+ CD4+ and CD8+ T cells compared to EC. Our data also show that elevated frequencies of CD8+CD38+HLA-DR+ T cells and CD14dimCD16+ monocytes were associated with both viremic control status and production of bNAbs. bNAb production was also strongly associated with increased frequency of CD57+HLA-DR+ CD8+ T cells, as well as decreased expression of chemokine receptors CCR2 and CX3CR1 on CD14dimCD16+ monocytes in VC compared to EC. Further studies are required to establish the cause and effect of alterations in monocyte populations during HIV-1 infection and whether these could tip the scale towards viral control below detectable levels.
Vicilin and 11s globulin cashew allergens share promiscous CD4+ T cell epitopes with other tree nuts (APP2P.100)
Authors: Archila Diaz Luis Diego , McGinty John , Chow I-Ting , Jeong David , Farrington Mary , Robinson David , Kwok William 
Published: January 2023

Abstract
Allergic reactions to cashew can be life threatening. While IgE-specific cashew epitopes have been studied, CD4+ T-cell specific epitopes for cashew remain uncharacterized. Additionally, cross-reactivity amongst tree nuts has not been examined in humans at the T-cell level. We sought to provide a thorough phenotypic analysis of cashew reactive T-cells in allergic and non-allergic subjects as well as to identify promiscuous epitopes among tree nut allergens. CD4+ T-cell responses by CD154 up-regulation assays indicate that cashew allergens Ana o 1 and Ana o 2 play a major role in cashew allergy. Multiple Ana o 1 and Ana o 2 T-cell epitopes were identified with the Tetramer-Guided Epitope Mapping approach. Direct ex vivo staining showed that the majority of Ana o 1 and Ana o 2-specific T-cells have a CCR4+ TCM (central memory) phenotype while a subset of these T-cells express CCR4+CCR6+ in allergic subjects. Conversely, in non-allergic subjects a CXCR3+ population was observed. Cashew-specific T-cell clones for several epitope regions responded robustly to hazelnut and pistachio but not to walnut, while some epitopes responded to cashew exclusively and were found to be species specific. Allergic responses to cashew could be triggered by cross-reactive tree nut epitopes, therefore, restricted consumption of tree nuts should be advised for cashew allergic subjects.
Comparison of systemic lupus erythematosus and healthy anti-nuclear antibody positive African-Americans reveals distinct differences in CD4+ and CD8+ T cell populations (BA3P.117)
Authors: Lu Rufei , Slight-Webb Samantha , Maecker Holden , Utz Paul , Guthridge Joel , James Judith 
Published: January 2023

Abstract
Systemic lupus erythematosus (SLE) is an autoimmune disorder arising from genetic and environmental factors that likely affect phenotypic and functional characteristics of multiple cell lineages. Almost all SLE individuals are antinuclear antibody positive (ANA+) although ANA positivity does not obligate autoimmune disease. The differences in cell physiology between ANA+ healthy individuals and individuals that go on to develop SLE remains a critical goal in understanding SLE development. We visualized the expression of 33 cellular markers through the hierarchical clustering of SPADE to provide a comprehensive view of the immune system between ANA- African Americans (n=8), ANA+ healthy controls (n=8) and ANA+ patients with SLE (n=8). In addition, the levels of 51 cytokines were measured in plasma using a multiplex immunoassay. Compared to healthy controls, SLE patients had lower frequencies of cytotoxic CD8+ T cells and regulatory CD4+ T cells (P&lt;0.05). Concentrations of serum sCD40 ligand were reduced in patients with SLE compared with ANA+ and ANA- healthy controls (p&lt;0.05). Interestingly, sCD40L production positively correlated with a decrease in regulatory CD4+ T cell populations (p&lt;0.01). IL-7 levels were lower in both ANA+ controls and SLE patients compared with ANA- healthy individuals (p&lt;0.05). Our results indicate that early differences in IL-7 may contribute to decreased levels of regulatory CD8+ and CD4+ T cells important for controlling systemic inflammation.
Type I interferons promote lupus through disruption of the lymphotoxin receptor-mediated mechanosensing MKL1 pathway in marginal zone macrophages (BA4P.124)
Authors: Mountz John , Li Hao , Hsu Hui-Chen , Zhou Yong , Wu Qi , Yang PingAr , Li Jun , Luo Bao , Morel Laurence , Ware Carl , Fu Yang , Yagita Hideo 
Published: January 2023

Abstract
Defective clearance of apoptotic cells (ACs) is a central pathogenic event in systemic lupus erythematosus (SLE). Here, we describe an underlying mechanism in which follicular translocation of marginal zone (MZ) B cells in the spleen of lupus BXD2 mice disrupts marginal zone macrophages (MZMs), which normally clear apoptotic debris and prevent entry of the AC antigens (AC-Ags) into the follicles. The phagocytosis of ACs by the spleen MZMs is enabled by a megakaryoblastic leukemia 1 (MKL1) transcription factor-mediated mechanosensing pathway. The MZ B cells maintain this pathway through their expression of membrane lymphotoxin-α1β2 (mLT). Follicular shuttling of mLT+ MZ B cells disengages their interaction with the LTβR+ MZMs, thereby downregulating MKL1 in the MZMs. This leads to defective F-actin polymerization, loss of their ability to clear ACs and eventually MZM dissipation. Type I interferon (IFN) signaling, a well-established clinical characteristic of SLE and is commonly considered as a downstream event of AC-Ag stimulation, is identified to play a key role in MZM erosion via promoting follicular shuttling of mLT+ B cells. Follicular translocation of MZ B cells, erosion of MZMs and loss of MKL1 were similarly identified in lupus B6.Sle1.Sle2.Sle3 mouse and human SLE spleens. Collectively, the results suggest that lupus might be interrupted by strategies that maintain or enhance mechanosensing signals in the MZM barrier to prevent follicular entry of AC-Ags.