bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B121: Oncogenic MYC contributes to tumor super-enhancers via eRNA amplification
Authors: Guo Yang Eric , Seyffert Michael , Abraham Brian , Ji Xiong , Young Richard 
Published: November 2016

Abstract
Super-enhancers (SEs) are large clusters of enhancers that control transcription of genes that define cell identity, and they are frequently acquired by cancer cells to drive key oncogenes. Indeed, the prominent oncogene MYC recurrently acquires SEs in many types of cancer, which may explain its overexpression in a broad array of cancers. Elevated levels of MYC promote transcriptional elongation at promoters of all active genes, thereby amplifying RNA output of the cellular gene expression program. High levels of MYC also lead to increased binding of MYC at enhancers, but the significance of enhancer invasion by MYC is unclear. Here, we propose a model that at tumor cell SEs MYC amplifies the production of enhancer RNAs (eRNAs), which in turn facilitate maintenance of SEs by stabilizing transcription factor and co-factor occupancy. We found that in Burkitt's lymphoma cells SEs depend on high levels of MYC and eRNAs, and that MYC is required for elevated levels of eRNA transcription. We demonstrate that eRNAs directly interact with RNA-binding transcription factors at SEs, and that perturbation of eRNA affects SE signal. Elevated MYC thus contributes to the dynamic formation and maintenance of SEs through amplification of eRNAs. Our results may identify novel RNA targets for new therapies for Burkitt's lymphoma, as well as other cancers. New ways to modulate the immune response may also be revealed by our studies.
Citation Format: Yang Eric Guo, Michael Seyffert, Brian Abraham, Xiong Ji, Richard Young. Oncogenic MYC contributes to tumor super-enhancers via eRNA amplification [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr B121.
Abstract B122: Molecular mechanism of V(D)J recombination from synaptic RAG1-RAG2 complex structures
Authors: Ru Heng , Chambers Melissa G. , Fu Tian-Min , Tong Alexander B. , Liao Maofu , Wu Hao 
Published: November 2016

Abstract
A hallmark of vertebrate immunity is the diverse repertoire of antigen-receptor genes that results from combinatorial splicing of gene coding segments by V(D)J recombination. The dimeric (RAG1-RAG2)2 recombinase (RAG) recognizes specific recombination signal sequences (RSSs), each containing a heptamer, a spacer of 12 or 23 base pairs, and a nonamer (12-RSS or 23-RSS). RAG only combines one 12-RSS and one 23-RSS, a dogma known as the 12/23 rule that governs the fidelity of V(D)J recombination. RAG introduces precise breaks at RSS-coding segment junctions to generate cleaved RSSs and hairpin coding segments. Here we report cryo-electron microscopy structures of multiple RAG complexes reconstituted with 12-RSS and 23-RSS intermediates and HMGB1 at up to 3.4 angstrom resolution. These structures reveal a closed conformation of RAG upon RSS synapsis, with base flipping and base-specific recognition of RSSs. Distortion at the RSS-coding segment junction and base flipping in the coding segment uncovers the geometry for a two-metal-ion catalytic mechanism. Both 12-RSS and 23-RSS are exceedingly bent by the bound HMGB1. The nonamer-binding domain dimer of RAG1 is flexibly attached to the active site dimer of RAG and is tilted towards the bent 12-RSS but away from the bent 23-RSS in the synaptic complexes, which provides an induced fit mechanism for the 12/23 rule. Collectively, our structures illustrate the elegant mechanisms of RAG-catalyzed V(D)J recombination at the molecular level.
Citation Format: Heng Ru, Melissa G. Chambers, Tian-Min Fu, Alexander B. Tong, Maofu Liao, Hao Wu. Molecular mechanism of V(D)J recombination from synaptic RAG1-RAG2 complex structures [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr B122.
Abstract B127: Free DNA and tolerance
Authors: Filaci Gilberto , Ferrera Francesca , Tardito Samuele , Altosole Tiziana , Bernardi Cinzia , Parodi Alessia , Fenoglio Daniela 
Published: November 2016

Abstract
Soluble DNA circulates in the peripheral blood of healthy subjects, and, at increased concentrations, of pregnant women and patients affected by tumors and vasculitis. Since the discovery of intracellular DNA sensors, inducing inflammatory responses after binding to DNA, DNA has been included among danger signals. However, this view does not explain the presence of abundant circulating DNA in conditions characterized by tolerance (pregnancy) or immunodeficiency (tumor). In order to verify whether DNA mediates also an immunoregulating activity, a 20 base-pair long oligonucleotide (poly-CG) was synthesized and tested for its capacity to: 1) bind MHC class II molecules; 2) exert immunoregulatory activity. The oligo binding to PMJ2-PC macrophages was inhibited by anti-MHC monoclonal antibodies (mAb). The specific binding of DNA to MHC class II molecules was confirmed by western blot analysis. Proliferation of OVA-specific splenocytes was inhibited by incubation with the oligo as well as by circulating DNA from cancer patients; moreover, fluorescent oligo, injected intravenously to NZB/W F1 mice, bound only on MHC class II positive cells (macrophages and B lymphocytes). Finally, nephritic NZB/W F1 mice, administered weekly with the oligo, showed delayed onset of protenuria and improved survival with respect to untreated animals, a phenomenon associated with increased frequencies of Treg. Interestingly, in vitro incubation of PMJ2-PC macrophages with the oligo induced increased CCL22 secretion. These data demonstrate for the first time that free DNA may mediate immunoregulatory activities.
Citation Format: Gilberto Filaci, Francesca Ferrera, Samuele Tardito, Tiziana Altosole, Cinzia Bernardi, Alessia Parodi, Daniela Fenoglio. Free DNA and tolerance [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr B127.
Abstract B128: Clinical translation of oncolytic measles virus for T cell activation
Authors: Engeland Christine E. , Veinalde Rūta , Kalle Christof von , Jaeger Dirk , Ungerechts Guy 
Published: November 2016

Abstract
The oncolytic measles virus (MeV) vaccine strain provides a flexible vector platform which allows for targeted, tumor-restricted immunomodulation. We have developed MeV vectors to support different phases of the cancer immunity cycle. This enables therapy directly tailored to the specific immune micromilieu of individual tumors.
We have validated MeV vectors for T cell activation in preclinical models. MeV encoding bispecific T cell engagers (BiTEs) recruit cytotoxic T cells to the tumor site. Tumor antigen-specific T cell activation is achieved with MeV oncolytic vaccines. MeV encoding IL-12 directs T cell responses towards a Th1 phenotype. Combining MeV with immune checkpoint inhibition increases the ratio of effector to regulatory T cells. Furthermore, our preclinical data support the notion that MeV-mediated oncolysis can break resistance to checkpoint antibodies.
A clinical Phase Ib/II trial combining MeV with an anti-PD1 antibody in patients with metastatic pancreatic adenocarcinoma is currently in preparation. Aside from safety and anti-tumor efficacy, a main focus of the trial is the accompanying translational research program. Sequential biopsies for analysis of tumor-infiltrating immune cells, cytokine and chemokine profiling, transcriptome and immunoreceptor sequencing are performed to identify biomarkers predictive of response.
Citation Format: Christine E. Engeland, Rūta Veinalde, Christof von Kalle, Dirk Jaeger, Guy Ungerechts. Clinical translation of oncolytic measles virus for T cell activation [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr B128.
Abstract B132: Importance and mechanism of poly(A) tail length-mediated translational control in different immune cells
Authors: Xiang Kehui , Bartel David 
Published: November 2016

Abstract
Translational control is an essential regulatory mechanism in immune cells. Although it has been suggested that poly(A) tail length-mediated translational control plays important roles in regulating select cytokine production in memory T cells and macrophages, whether this is a transcriptome-wide regulatory principle in all immune cells remains unknown. We set out to perform RNA-seq, ribosome-footprint profiling and poly(A) tail length profiling across major types of immune cells to examine the relationship between poly(A) tail length and translational efficiency in these systems. We also plan to delineate the transcriptome-wide landscape of poly(A) tail length before and after immune activation, and investigate if the coupling of poly(A) tail length and translational efficiency plays a regulatory role in this process.
Meanwhile, to understand the general mechanistic details of how poly(A) tail length affects translational efficiency in a cell context-dependent manner, we carried out RNA pull-down experiments and isolated proteins from known coupled (Xenopus oocytes) and uncoupled (rabbit reticulocyte lysates) systems. By quantitative mass spectrometry analysis, we identified key factors that are responsible for coupling translational efficiency to poly(A) tail length. Among these candidates, poly(A) binding protein (PABPC1) plays an essential role. Overexpression of PABPC1 in Xenopus oocytes renders the translation of reporter RNAs with either a short poly(A) tail or a long poly(A) tail equally well, turning a coupled system into an uncoupled system. We have also generated an effective degron-induced PABPC1-knockdown cell line and are performing analysis to see if the coupling can be established in a normally uncoupled system. Our results suggest that cells can modify the expression of PABPC1 to help determine if poly(A) tail length regulates translational efficiency.
Citation Format: Kehui Xiang, David Bartel. Importance and mechanism of poly(A) tail length-mediated translational control in different immune cells [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr B132.
Abstract B138: Immunotherapy effect on survival of acute myeloid leukemia patients
Authors: Shi Runhua , Li Teena , Shi Lawrence , Mills Glenn 
Published: November 2016

Abstract
Background: Immunotherapy has been used to treat many cancers for years. It has been combined with other treatments such as chemotherapy and stem cell transplant. The purpose of the current study is to assess the impact of immunotherapy and payer status on Acute Myeloid Leukemia (AML) patient survival.
Patients and Methods: Patients in the National Cancer Data Base who were registered between 2004 and 2012 and followed up to the end of 2013 were used in this research. We evaluated a cohort of 50272 AML patients between the ages of 18 to 65 years old who did not undergo radiation or hormonal therapy. The effect of treatments (immunotherapy, stem cell transplant, and adjuvant chemotherapy) on the survival of AML was investigated. Additional variables adjusted included sex, age, race, Charlson Comorbidity Index, education, income, payer status, distance traveled, facility type, diagnosing/treating facility, and treatment delay. Multivariate Cox regression was used to investigate the effect of immunotherapy on the survival of AML patients while adjusting for other factors.
Results: The mean age of the patients was 49 years (SD = 12) old. The proportion of patients that received treatments were immunotherapy (1.47%), stem cell transplant (6.11%), and chemotherapy (74.43%). The median overall survival for all patients was 8.76 years. While using multivariate analysis to adjust for other factors, effects of treatment on survival were significant for chemotherapy (hazard ratio (HR) = 1.7, 95% CI: 1.49-2.0), immunotherapy (HR = 0.87, 95% CI: 0.76-0.99), and stem cell transplant (HR = 0.946, 95% CI: 0.88-1.01). While adjusting for other factors, patients who received immunotherapy had a reduced risk of death by 13% compared to patients without immunotherapy whereas patients who received chemotherapy had an increased risk of death by 70% compared to patients without chemotherapy. In addition, compared to patients with private insurance, the HR were 1.38, 1.43, and 1.2 for Medicaid, Medicare and uninsured patients, respectively and were all statistically significant. Compared to patients with a Comorbidity Index score of 0, the HR were 1.35 and 1.71 for Comorbidity Index score of 1 and 2+, respectively.
Conclusion: Immunotherapy was found to be a significant benefactor in the survival of AML patients. In addition, payer status and Comorbidity index score were also significant predictors for the survival of AML patients.
Citation Format: Runhua Shi, Teena Li, Lawrence Shi, Glenn Mills. Immunotherapy effect on survival of acute myeloid leukemia patients [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr B138.
Abstract B141: Targeting the complement system to improve radiation treatment
Authors: Olcina Monica M. , Giaccia Amato J. 
Published: November 2016

Abstract
The standard of care for a variety of cancers consists of therapies that are associated with significant toxicity, however, relatively little is known regarding what strategies could be undertaken to reduce treatment toxicity without compromising tumor control. We aim to establish whether targeting the complement system could be used to minimize treatment toxicity while improving tumor sensitivity to radiation. Complement is an important pathway in immunity; however, its inappropriate activation may result in tissue injury. Our data suggests that in response to radiotherapy, expression of complement regulators is decreased significantly in normal colon. Importantly, these expression changes correlate with an increase in the C5b-9 complex (thought to be responsible for cell lysis) in irradiated colon in vivo. Furthermore, our results suggest that targeting the complement system (either genetically or pharmacologically) can result in increased survival of mice following radiotherapy, through protection of the gastrointestinal tract from radiation-induced toxicity.
Citation Format: Monica M. Olcina, Amato J. Giaccia. Targeting the complement system to improve radiation treatment [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr B141.
Abstract IA04: T cell recognition and tumor resistance in human cancer
Authors: Schumacher Ton 
Published: November 2016

Abstract
The T cell-based immune system has evolved to recognize and destroy cells that differ from “self” on the basis of the antigens they express. Many human tumors contain large numbers of mutations, of which many hundreds can be present within expressed genes. As the resulting altered protein sequences are foreign to the immune system, immune recognition of such “neo-antigens” has been proposed as a major factor in the activity of clinically used immunotherapeutics such as anti-CTLA-4 and anti-PD-1.
In support of this hypothesis, using in-house developed technologies we have demonstrated that both CD4 and CD8 T cell recognition of the consequences of DNA damage is a common feature in human melanoma and can be boosted by T cell checkpoint blockade. Furthermore, to extend these data to other tumor types, we have benchmarked the foreign antigenic space in a variety of human cancers against a series of human pathogens. Collectively, these data, and data from other groups, establish “tumor foreignness” as one of the critical determinants in effective cancer immunotherapy.
Clearly, the sensitivity of tumor cells to the tumor-specific T cell pool that can be present in intrinsically foreign tumors forms an additional requirement for tumor control. To address factors that control such sensitivity, we a currently determining mechanisms of immune escape upon T cell targeting of human tumors. Results from this analysis are expected to contribute to the further definition of biomarkers that predict the outcome of the interaction between human tumors and the T cell-based immune system.
Citation Format: Ton Schumacher. T cell recognition and tumor resistance in human cancer [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr IA04.
Abstract IA05: Targeting regulatory T cells in tumors
Authors: Vignali Dario A. 
Published: November 2016

Abstract
Regulatory T cells (Tregs) inhibit beneficial antitumor responses. Treg depletion enhances tumor rejection in animal models and the clinic but also leads to substantial adverse events. Thus approaches have been sought to target Tregs in tumors while limiting systemic autoimmune and inflammatory manifestations. Two approaches will be discussed. First, the signals that maintain Treg stability and potentiate their function remain obscure. We have shown that the immune cell surface ligand semaphorin-4a (Sema4a) on conventional T cells and DCs, and the Treg-restricted receptor neuropilin-1 (Nrp1) interact to potentiate Treg function. Mice with a Treg-restricted deletion of Nrp1 exhibit limited tumor-induced tolerance and thus substantial resistance to tumors, yet do not develop any autoimmune manifestations. Thus, Nrp1 ligation maintains Treg stability and function in highly inflammatory sites but is dispensable for the maintenance of immune homeostasis, highlighting Nrp1 as a potential immunotherapeutic target in cancer. Second, the relative importance of different Treg suppressive mechanisms remains contentious. Interleukin-35 (IL35) is a Treg-secreted cytokine known to inhibit effector T cell proliferation and mediate infectious tolerance via induction of suppressive IL35-producing induced Tregs, iTr35. Using antibody-mediated neutralization, Treg-restricted deletion of Ebi3 and novel reporter mice, we have shown that IL35 facilitated tumor growth by limiting antitumor immunity in transplantable and genetically-induced murine models of melanoma and lung carcinoma. These findings reveal the previously unappreciated importance of IL35 in limiting antitumor immunity and present IL35 as a potential therapeutic target in cancer.
Citation Format: Dario A. Vignali. Targeting regulatory T cells in tumors [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr IA05.
Abstract IA06: Molecular basis of T cell exhaustion: Insights for immunotherapy
Authors: Wherry E. John 
Published: November 2016

Abstract
T cell exhaustion is common during chronic infections, cancer and prevents optimal immunity. Exhausted CD8 T cells (TEX) are defined by the loss of ability to perform effector functions efficiently, low proliferative capacity, and poor survival following antigen stimulation. In addition, it has become clear that TEX co-express multiple inhibitory receptors that negatively regulate their function. Indeed, receptors such as PD-1 have become major targets of clinical immunotherapies in cancer and infectious disease aimed at re-invigorating TEX. Our work has recently defined transcriptional networks of T cell exhaustion and has focused on the role of key transcription factors, including T-bet and Eomesodermin (Eomes) in controlling the sustainability and terminal differentiation of TEX populations. We have found a key role for T-bet in sustaining a progenitor pool of TEX during chronic infection, while the related transcription factor Eomes governs terminal differentiation. One key observation from these studies is that a key surrogate of reinvigoration of TEX responses is a population of EomesHi PD-1Hi TEX. The use of this subset of CD8 T cells as a biomarker is explored. Moreover, our recent work has investigated the question of durability of response to PD-1 pathway blockade. These studies have lead to the discovery that the epigenetic landscape of TEX is highly distinct from effector or memory CD8 T cells defining TEX as a unique and distinct lineage of cells. Moreover, we have now defined the epigenetic and transcriptional network changes that occur in TEX upon PD-1 blockade and the effects of these changes on long-term durability of TEX reinvigoration. Ultimately, a more precise molecular understanding of T cell exhaustion should lead to novel and more robust clinical interventions to reverse exhaustion in settings of persisting infections and cancer.
Citation Format: E. John Wherry. Molecular basis of T cell exhaustion: Insights for immunotherapy [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr IA06.
Abstract IA11: Emerging insights into stromal cell function inimmune homeostasis and inflammation
Authors: Turley Shannon 
Published: November 2016

Abstract
Stromal cells reside in all bodily organs and have long been viewed as chief structural determinants of tissue organization, function, and regeneration. It is becoming increasingly clear that lymphoid organs contain a developmentally related network of highly specialized myofibroblasts known as fibroblastic reticular cells (FRCs). Our understanding of lymph node and spleen FRC function in immune homeostasis and inflammatory disease is incomplete; however, emerging evidence suggests that these cells are of central importance in immunity and tolerance. Likewise, the precise impact of inflammation on stromal cell numbers, activation, gene expression, and function in situ remains unclear. Using genetic and molecular approaches that target specific subsets of stromal cells in vivo we have begun to examine the identity, plasticity, and immunological functions of FRCs in healthy, inflamed, and malignant tissues. We are systematically defining gene expression and molecular elements that control the activation of FRCs across multiple lymphoid and non-lymphoid organs. Additional studies examining the spatial contexture and molecular interactions between fibroblastic reticular cells and immunocytes have identified previously unknown and functionally significant cross-talk between these compartments in health and inflammatory disease settings. New findings from this work will be presented.
Citation Format: Shannon Turley. Emerging insights into stromal cell function inimmune homeostasis and inflammation [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr IA11.