bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B109: Broadly neutralizing antibodies against HCV use a CDRH3 disulfide motif to recognize an E2 glycoprotein site that can be targeted for vaccine design
Authors: Flyak Andrew I. , Ruiz Stormy , Colbert Michelle , Luong Tiffany , Crowe James E. , Bailey Justin R. , Bjorkman Pamela J. 
Published: February 2019

Abstract
Hepatocellular carcinoma is the most common type of liver cancer and is responsible for approximately one million deaths each year. In the United States, persistent infection with hepatitis C virus (HCV) is among the leading causes of hepatocellular carcinoma. HCV vaccine efforts are hampered by genetic diversity of HCV envelope glycoproteins E1 and E2. Structural studies of broadly neutralizing antibodies (bNAbs) (e.g., HEPC3 and HEPC74) isolated from individuals who spontaneously cleared HCV infection will facilitate immunogen design to elicit antibodies against multiple HCV variants. However, challenges in expressing HCV glycoproteins previously limited bNAb-HCV structures to complexes with truncated E2 cores.New expression and purification techniques allowed us to produce bNAb complexes with full-length E2 ectodomains for structural studies. We solved crystal structures of HEPC3 and HEPC74 alone and complexed with E2 ectodomains. We measured the binding and neutralization potency of HEPC3/HEPC74-like germline precursors. Despite derivation from different individuals, HEPC3 and HEPC74 use the same germline heavy chain gene segments and possess a limited number of somatic mutations. We describe a shared CDRH3 disulfide motif that exhibits common interactions with a conserved epitope in the front layer of E2. The germline-encoded CDRH3 motif plays a critical role in initial recognition of HCV by naïve B cells. The structures of E2 ectodomain reveal regions (including a target of immunogen design) that were truncated or disordered in E2 core. We also identify candidate immunogens: E2 variants that bind to HEPC3/HEPC74-like germline precursors. These data reveal unusual structural features relevant to the fundamental understanding of antibody-antigen interactions. The identification of common genetic signatures of HCV bNAbs will facilitate lineage-targeted immunogen design to raise bNAbs against the conserved epitope in the E2 front layer.
Citation Format: Andrew I. Flyak, Stormy Ruiz, Michelle Colbert, Tiffany Luong, James E. Crowe, Jr., Justin R. Bailey, Pamela J. Bjorkman. Broadly neutralizing antibodies against HCV use a CDRH3 disulfide motif to recognize an E2 glycoprotein site that can be targeted for vaccine design [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr B109.
Abstract B125: Targeting human CD141+ DC using CLEC9A antibodies for cancer immunotherapy
Authors: Radford Kristen , Pearson Frances , Masterman Kelly-Anne , Tullett Kirsteen , Haigh Oscar , Walpole Carina , Daraj Ghazal , Rojas Ingrid Leal , Lahoud Mireille 
Published: February 2019

Abstract
Dendritic cells (DC) are a heterogeneous cell population, with specialist subtypes driving specific immune responses. In mice, the cDC1 subset (also referred to as Batf3-dependent DC, XCR1+ DC, CD8+ DC in lymphoid tissues and CD103+ DC in peripheral tissues) is essential for the induction of tumor immune responses and for the efficacy of checkpoint inhibitor blockade and adoptive T-cell immunotherapies. Vaccines that can deliver antigens (Ag) directly to DCs in vivo are more effective than cell-based therapies in mouse models and are promising approaches to translate to humans. CD141+ DC are the human cDC1 equivalent and specifically express the C-type lectin-like receptor CLEC9A, that facilitates cross-presentation of dead cell Ag. Targeting tumor-associated Ag (TAA) to human CD141+ DC using CLEC9A antibody (Ab) is therefore an attractive strategy to induce or boost tumor immune responses. NYESO1 and WT1 are well characterised, highly immunogenic TAA expressed by a broad array of tumor types. We developed recombinant human chimeric IgG4 Ab specific for human CLEC9A genetically fused to NYESO1 or WT1. For comparison we developed TAA fusions with chimeric IgG4 Ab specific for human DEC-205, which is expressed by many human leukocytes, and β-galactosidase as an irrelevant isotype control. CLEC9A-NYESO1 and CLEC9A-WT1 Abs retained their binding specificity for CD141+ DC. Following uptake of CLEC9A-WT1, CD141+ DC cross-presented a WT-1 HLA-A24-restricted epitope for recognition by specific CD8+ cytotoxic T-cells. Likewise, a HLA-A2-restricted NYESO1 epitope was cross-presented Ag specific CD8+ T-cells by CD141+ DC following uptake of CLEC9A-NYESO1. For both TAA, the CLEC9A Abs were more efficient at delivery of Ag for cross-presentation than DEC-205 or isotype control Abs. Moreover, using a humanized mouse model in which functional human CD141+ DC and Ag-specific T-cells develop, CLEC9A-TAA Ab induced priming of Ag-specific T-cells. Our data advocate further development of human CLEC9A targeting Abs as cancer vaccines.
Citation Format: Kristen Radford, Frances Pearson, Kelly-Anne Masterman, Kirsteen Tullett, Oscar Haigh, Carina Walpole, Ghazal Daraj, Ingrid Leal Rojas, Mireille Lahoud. Targeting human CD141+ DC using CLEC9A antibodies for cancer immunotherapy [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr B125.
Abstract B129: Human endogenous retroviruses as a potential reservoir for T-cell mediated cancer immunotherapy
Authors: Saini Sunil Kumar , Bjerregaard Anne-Mette , Ørskov Andreas D. , Unnikrishnan Ashwin , Holmberg Staffan , Anande Govardhan , Bentzen Amalie Kai , Szallasi Zoltan , Eklund Aron C. , Grønbæk Kirsten , Hadrup Sine Reker 
Published: February 2019

Abstract
Epigenetic modulation using DNA methyltransferase inhibitors (DNMTis), such as 5-azacytidine (5-aza-CR), have been shown to affect the cellular immunogenicity in vitro through upregulations of human endogenous retroviruses (HERV) leading to activation of the INFγ response pathway. HERVs comprise up to 8% of the human genome, and may hold a large reservoir of potential tumor antigens.We examined the in vivo efficacy of 5-aza-CR in terms of upregulations of HERV expression during standard treatment regimen, as well as the ability of such HERV transcripts to form T-cell antigens leading to measurable T-cell recognition upon treatment. We have studied 66 HERV genes that have been shown to be transcribed in human tissues. To identify HERV derived immune recognition, we generated a library of 1169 HERV derived potential antigenic peptides restricted to most abundant MHC class I molecules in the Caucasian population. Peripheral blood mononuclear cells (PBMCs) from a cohort of 19 patients and bone marrow samples from a cohort of 11 patients, treated with DNMTis for different hematological malignancies (MDS, AML, and CMML) were used to detect CD8+ T-cells reactive to ERV-derived peptides. We detected CD8+ T-cells specific to several HERV-derived peptides both in healthy and diseased individuals. Further, in an additional cohort of patients we examined expression level of these HERVs by RNA seq analysis and compared with healthy individuals demonstrating a disease associated upregulation of HERVs in hematological malignancies. Presence of T-cells reactive to HERV antigens and enhanced expression of HERVs in these malignancies suggest that HERVs may indeed provide a pool of shared tumor associated antigens. These antigens could potentially be enhanced through DNMTi treatment and may provide a target for T-cell mediated immunotherapy.
Citation Format: Sunil Kumar Saini, Anne-Mette Bjerregaard, Andreas D. Ørskov, Ashwin Unnikrishnan, Staffan Holmberg, Govardhan Anande, Amalie Kai Bentzen, Zoltan Szallasi, Aron C. Eklund, Kirsten Grønbæk, Sine Reker Hadrup. Human endogenous retroviruses as a potential reservoir for T-cell mediated cancer immunotherapy [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr B129.
Abstract B146: The tumor necrosis factor superfamily member RANKL suppresses effector cytokine production in group 3 innate lymphoid cells
Authors: Bando Jennifer Kaoru , Gilfillan Susan , Song Christina , McDonald Keely , Huang Stanley C-C. , Newberry Rodney D. , Kobayashi Yasuhiro , Allan David S.J. , Carlyle James R. , Cella Marina , Colonna Marco 
Published: February 2019

Abstract
While signals that activate group 3 innate lymphoid cells (ILC3s) have been described, the factors that negatively regulate these cells are less well understood. Here we found that the tumor necrosis factor (TNF) superfamily member receptor activator of nuclear factor κB ligand (RANKL) suppressed ILC3 activity in the intestine. Deletion of RANKL in ILC3s and T-cells increased C-C motif chemokine receptor 6 (CCR6)+ ILC3 abundance and enhanced production of interleukin-17A (IL-17A) and IL-22 in response to IL-23 and during infection with the enteric murine pathogen Citrobacter rodentium. Additionally, CCR6+ ILC3s produced higher amounts of the master transcriptional regulator RORγt at steady state in the absence of RANKL. RANKL-mediated suppression was independent of T-cells, and instead occurred via interactions between CCR6+ ILC3s that expressed both RANKL and its receptor, RANK. Thus, RANK-RANKL interactions between ILC3s regulate ILC3 abundance and activation, suggesting that cell clustering may control ILC3 activity.
Citation Format: Jennifer Kaoru Bando, Susan Gilfillan, Christina Song, Keely McDonald, Stanley C-C. Huang, Rodney D. Newberry, Yasuhiro Kobayashi, David S.J. Allan, James R. Carlyle, Marina Cella, Marco Colonna. The tumor necrosis factor superfamily member RANKL suppresses effector cytokine production in group 3 innate lymphoid cells [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr B146.
Abstract B150: STING acquired species-specific motifs to control alternative immune responses
Authors: Mann Carina C. de Oliveira , King David S. , Kranzusch Philip J. 
Published: February 2019

Abstract
Stimulator of Interferon Genes (STING) is an adaptor protein critical for downstream signaling during recognition of mislocalized cytosolic DNA. STING activation requires recognition of a unique second messenger 2′–5′, 3′–5′ cyclic GMP–AMP (2′3′ cGAMP) synthesized by the pathogen recognition receptor cyclic GMP–AMP synthase (cGAS). Due to its broad expression in most tissues, and ability to respond to different endogenous and foreign small molecules, STING is emerging as a promising drug target for cancer immunotherapy and treatment of autoimmune diseases. However, it remains unknown how the single adaptor protein STING controls distinct transcriptional outputs leading to production of type I interferon, proinflammatory cytokine responses or autophagy. Here we present surprising evidence for the ancient origins of the cGAS-STING signaling pathway by discovery of bacterial cGAS-like enzymes and complete functional cGAS-STING pathways in lower metazoans. Our previous structural data demonstrate that human and metazoan STING proteins share a common architecture that couples ligand binding with conformational changes and allows signal activation. However, it remained unclear how alternative STING conformations control different downstream signaling outputs, and which motifs are responsible for recruitment of the downstream factors controlling each pathway. We have now combined a phylogenetic and biochemical approach to explain the conserved elements that regulate STING downstream signaling events. Our analysis identifies new immune pathway-specific regulatory motifs acquired by distinct STING species, and we are currently focused on identifying the recruited factors important for controlling human STING signaling. Together, our results explain the molecular basis for distinct STING downstream signaling, and provide new insights for the rational design of STING pathway-specific therapeutics.
Citation Format: Carina C. de Oliveira Mann, David S. King, Philip J. Kranzusch. STING acquired species-specific motifs to control alternative immune responses [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr B150.
Abstract B155: Impact of transcription initation on translation regulation by the mTOR pathway
Authors: Duttke Sascha H. , Chang Max , Glass Christopher K. , Berman Andrea , Benner Christopher 
Published: February 2019

Abstract
The two major processes of eukaryotic gene expression, transcription and translation, are spatially and temporally separated and commonly perceived to be independently regulated. Unexpectedly, the analysis of nascent transcription start sites (TSSs) genome-wide, proposes that alternative TSS can target mRNAs of the same gene to distinct modes of translational regulation.Our preliminary data found the TCT core promoter motif to function as a transcriptionally suboptimal Initiator (Inr) motif. Despite the rapid turnover of most regulatory elements, the TCT motif is remarkably conserved among the promoters of orthologous bilaterians genes. However, the translation of mRNAs starting from TCT but not Inr promoters is preferentially regulated by the Mammalian target of rapamycin complex 1 (mTORC1), likely via the La-related protein 1 (Larp1) that binds mRNAs starting on pyrimidine but not purines. These findings reveal a functional dependency between transcription initiation and translation regulation, and highlight the importance of TSS selection in promoters. Inhibitors of mTORC1, and more recently Larp1, are rapidly moving into clinical cancer therapy trials but did not live up to the expectations in patients. Markers for patient stratification and predicting mTOR inhibitor efficacy are needed. As TSSs reflect the integrated signals of gene regulatory pathways and also appear to impact translational regulation, our future research will address how far alternative TSSs facilitate acquired resistance to mTOR inhibitors in tumors and 2) TSSs can serve as a predictive marker for mTOR inhibitors efficacy.
Citation Format: Sascha H. Duttke, Max Chang, Christopher K. Glass, Andrea Berman, Christopher Benner. Impact of transcription initation on translation regulation by the mTOR pathway [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr B155.
Abstract B168: A Radiosensitivity gene signature and PD-L1 status predict clinical outcome of patients with glioblastoma multiforme in The Cancer Genome Atlas Dataset
Authors: Kim Inah , Jang Bum Sup 
Published: February 2019

Abstract
Background: A combination of radiotherapy and immune checkpoint blockade, such as programmed death-1 (PD-1) or programmed death-ligand 1 (PD-L1) blockade, is being actively tested in clinical trial settings. Here, we tried to identify a subset of patients that could potentially benefit from this strategy using The Cancer Genome Atlas (TCGA) dataset for glioblastoma (GBM). Methods: A total of 399 cases were clustered into radiosensitive (RS) versus radioresistant (RR) groups based on radiosensitivity gene signature and were further stratified into PD-L1 high versus PD-L1 low groups according to the median expression of CD274 mRNA. Differential and integrated analyses with expression and methylation data were performed. CIBERSORT was used to enumerate the immune repertoire that resulted from transcriptome profiles. Results: We identified a subset of GBM patients, the “PD-L1 high-RR group” that had a worse clinical outcome compared to the other groups. In this group, differentially expressed genes (DEG) were highly enriched for an immune response and mapped into activation of PI3K-AKT and MAPK signaling pathways. Through integration of DEG and differentially methylated regions, kinase MAP3K8, which is involved in T-cell receptor signaling, was found to be upregulated, while BAI1, a factor that inhibits angiogenesis, was silenced. CIBERSORT showed that a higher infiltration of the immune repertoire, which included M2 macrophages and regulatory T-cells, contributed to an immunosuppressive tumor microenvironment. Conclusion: Looking at the results collectively, the “PD-L1-high-RR group” could potentially benefit from radiotherapy combined with PD-1/PD-L1 blockade and angiogenesis inhibition.
Citation Format: Inah Kim, Bum Sup Jang. A Radiosensitivity gene signature and PD-L1 status predict clinical outcome of patients with glioblastoma multiforme in The Cancer Genome Atlas Dataset [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr B168.
Abstract B171: Elucidating the mechanism of RAG tracking and its impacts on V(D)J recombination
Authors: Lee Cheng-Sheng , Hu Jiazhi , Alt Frederick W. 
Published: February 2019

Abstract
RAG endonuclease initiates V(D)J recombination by binding to the recombination signal sequences (RSSs), introducing DNA breaks between two V(D)J gene segments, and mediating their joining. This process is tightly regulated to generate diverse antigen receptor repertoires and prevent aberrant events that could cause genomic translocations/deletions and lymphoid cancer. RAG can track directionally over chromosomal loop domain in which they reside. Tracking is evidenced by cleavage/joining of short cryptic RSSs lying exclusively in convergent orientation to a bona fide RSS. However, the mechanism of RAG tracking and its impacts remain unknown. Here I established an unbiased assay system by utilizing allele-specific barcode and employing high throughput genome-wide translocation sequencing (HTGTS) to quantitatively evaluate RAG-mediated recombination frequency. I found that insertion of one single bona fide RSS is sufficient to initiate RAG tracking in the c-Myc domain and the recombination between the RSS and its cryptic RSSs seems to follow the 12/23 rule to some degree. When ectopically inserted bona fide RSS pair is 0.5kb apart, convergent configuration of the RSS pair is 4.8-fold more frequent than the tandem configuration. When the distance increases to 267kb, the difference increases to 14-fold, suggesting the contribution of RAG tracking over diffusion-based mechanism increases when the distance between RSS pair increases. In addition, the presence of CTCF-binding element promotes recombination by more than 10-fold. Depletion of Wapl, cohesin remover, to disrupt cohesin turnover reduces V(D)J recombination. The distal RSSs are much preferentially affected. The data suggest that RAG tracking may be driven by cohesin sliding along chromatin.
Citation Format: Cheng-Sheng Lee, Jiazhi Hu, Frederick W. Alt. Elucidating the mechanism of RAG tracking and its impacts on V(D)J recombination [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr B171.
Abstract B172: Molecular mechanisms of dual-specificity phosphatase 22 (DUSP22) in suppression of tumorigenesis: The potential involvement of the EGFR/PD-L1 axis
Authors: Lin Wen-Jye , Chang Cheng-Wei , Lin Hsiu-Ping , Ho Hui-Min 
Published: February 2019

Abstract
DUSP22, belonging to members of the dual-specificity phosphatases (DUSPs) family, can control the activity of various protein kinases and transcription factors through the dephosphorylation process. Many DUSP22-targeted proteins are involved in signaling pathways that are crucial for tumorigenesis, and inflammation. Genetic alteration of DUSP22 or DUSP22 downregulation was observed in some cancers. However, little is known about the roles of DUSP22 during tumor suppression. Here, utilizing TGCA databases, our analysis showed low DUSP22 expression is associated with shorter disease-free survival of lung and prostate cancer patients. The IL-6/STAT3 and EGFR/ERK1/2 axes are generally recognized as an important oncogenic and mitogenic pathway in prostate cancer. We found that DUSP22 expression markedly reduced p-STAT3 (Tyr705), and p-EGFR (Tyr1068)/p-ERK1/2 expression levels after IL-6 and EGF stimulation, respectively, in prostate cancer cells. Similarly, DUSP22 can inhibit the EGFR/ERK1/2 axis in lung cancer cells that harbor EGFR exon 19 deletion mutation, supporting a repressive role for DUSP22 in regulating growth receptor signaling pathways. In addition, we found the exogenous expression of DUSP22 significantly reduced the cell growth of prostate and lung cancer cells. More importantly, DUSP22 can serve as a negative regulator of androgen receptor in prostate cancer cells through reducing EGF-induced AR phosphorylation and inhibiting DHT-mediated nuclear AR translocation. Taken together, our current data indicate that loss of DUSP22 function or DUSP22 downregulation may accelerate lung and prostate tumorigenesis through EGFR-dependent pathways. Importantly, it has been reported that increased PD-L1 expression by EGFR activation mediates the immune escape in EGFR-driven lung cancer (NSCLC). We found that the inhibition of the EGFR signaling by DUSP22 can reduce PD-L1 expression in both lung and prostate cancer cells, suggesting that loss of DUSP22 function in cancer cells may not only enhance cell growth, but also potentially repress antitumor immunity through upregulation of PD-L1. Our findings implicate that anti-PD1/PD-L1 therapy could be a potential option if lung or prostate cancer patients are found with low DUSP22 expression. Currently, we are using multiple approaches to elucidate molecular mechanisms of DUSP22 ablation for accelerating lung and prostate tumorigenesis in vivo.
Citation Format: Wen-Jye Lin, Cheng-Wei Chang, Hsiu-Ping Lin, Hui-Min Ho. Molecular mechanisms of dual-specificity phosphatase 22 (DUSP22) in suppression of tumorigenesis: The potential involvement of the EGFR/PD-L1 axis [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr B172.