bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A138: Identification of key immune regulators that control obesity-induced liver inflammation and diseases
Authors: Zhong Zhenyu , Umemura Atsushi , Liang Shuang , Karin Michael 
Published: May 2016

Abstract
Obesity has become a major risk factor for a number of human diseases, including cancer. Amongst different types of malignancies, obesity appears to have the highest association-rate with hepatocellular carcinoma (HCC), the dominant form of primary liver cancer. Obesity-induced sterile inflammation is the key switch mediating the transition from hepatic steatosis to steatohepatitis (non-alcoholic steatohepatitis, NASH) and HCC. However, the molecular mechanism underlying obesity-induced hepatic inflammation remains poorly understood. We show that fat accumulation increases liver damage and release of DAMP (damage-associated molecular patterns) from dying hepatocytes, to amplify inflammation and accelerate hepatic disease progression. These DAMP induce mitochondrial reactive oxygen species (mtROS) in macrophages, which direct inflammatory cytokine/chemokine production in a manner that requires activation of a calcium permeable channel, TRPM2 (transient receptor potential melastatin 2). Blockade of mtROS generation, removal of extracellular calcium or ablation of TRPM2 expression in macrophages abolished DAMP-induced inflammatory cytokine/chemokine production, suggesting that a “mtROS-TRPM2” pathway drives DAMP-induced inflammation. Moreover, we identified HMGB1 as the key DAMP released from lipid-damaged hepatocytes. By using HMGB1 neutralizing antibody, we found it suppressed HMGB1 expression in the liver of MUP-uPA mice (an animal model for human NASH), and markedly attenuated liver damage, accumulation of lipid droplets, inflammation, and fibrosis, which represent typical features of human NASH. These results also suggest that HMGB1 is a key component of a vicious autoregulatory cycle triggered by HFD consumption, that mains ER stress and liver inflammation, as well as elevated HMGB1 expression and release.
Citation Format: Zhenyu Zhong, Atsushi Umemura, Shuang Liang, Michael Karin. Identification of key immune regulators that control obesity-induced liver inflammation and diseases. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr A138.
Abstract A156: Anti-p53 auto-antibody serum profiling using high-density peptide arrays
Authors: Lo Ken C. , Tan John C. , Sullivan Eric , Bannen Ryan , Richmond Todd , Grupp Florian , Weiser Stefan , Heindl Dieter , Stengele Klaus-Peter , Thomas Albert 
Published: May 2016

Abstract
Cancer is a result of a number of genetic alterations that disturb normal, controlled cell growth and differentiation. Mutational events leading to the activation of oncogenes or the inactivation of tumor-suppressor genes have been linked causally to the formation of tumors. p53 is one of the most important regulators of transcription, cellular cycle, DNA repair and apoptosis detected to date. Anti-p53 antibodies have been detected in the serum of cancer patients. This immune response is probably due to a self-immunization process linked to the strong immunogenicity of the p53 protein, and is associated predominantly with p53 missense mutation and p53 accumulation in the tumor. Auto-antibodies have also been proposed as potential diagnostic biomarkers for early stage diagnosis of cancers, since an increase in serum levels of certain auto-antibodies has been shown to precede the development of disease symptoms and correlate with cancer incidence for various cancers including breast and lung cancer.
Here we systematically evaluate reactivity of antibodies in p53 positive serum samples and identify reactive epitopes to normal and mutant peptides using a high-density (2.9 Million) peptide microarray. We assess the effect of linker length, peptide length, and flanking serines on antibody detection. We propose peptide array design parameters that can be applied to a whole proteome level to enable biomarker discovery and validation of novel auto-antibody epitopes associated with cancer.
Citation Format: Ken C. Lo, John C. Tan, Eric Sullivan, Ryan Bannen, Todd Richmond, Florian Grupp, Stefan Weiser, Dieter Heindl, Klaus-Peter Stengele, Albert Thomas. Anti-p53 auto-antibody serum profiling using high-density peptide arrays. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr A156.
Abstract A166: Biogenesis and regulatory functions of super-enhancer RNAs in cancer cells of the immune system
Authors: Guo Yang Eric , Young Richard 
Published: May 2016

Abstract
Super-enhancers (SEs) are large (2 to &gt;100 kilobases) DNA elements that control cell identity and disease. These unusual elements are occupied by high levels of key transcription factors, co-activators and chromatin regulators. SEs are hot spots for sequence variations associated with many human diseases, including cancer. Surprisingly, SEs are transcribed at high levels into RNAs (seRNAs). However, little is known about the biogenesis, structural identity and function of these seRNAs. Preliminary evidence suggests that seRNAs are components of SE complexes, composed of chromatin, RNAs and transcription factors, which play critical roles in controlling expression of key master cell-type-specific transcription factors and disease-causing genes. Our main objectives are to characterize the biogenesis of seRNAs, to determine the composition of RNA-protein complexes associated with seRNAs and to investigate the functions of seRNAs in gene regulation. We are focusing on the c-MYC and RUNX1 SEs, drivers of two cancers originating from B and T cells of the immune system: multiple myeloma (MM) and T-cell acute lymphoblastic leukemia (T-ALL), respectively. By uncovering the biogenesis and functions of seRNAs at the molecular level, our results may identify novel targets for new therapies for MM and T-ALL, as well as other cancers. New ways to modulate the immune response may also be revealed by our studies.
Citation Format: Yang Eric Guo, Richard Young. Biogenesis and regulatory functions of super-enhancer RNAs in cancer cells of the immune system. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr A166.
Abstract A167: Functional analysis of DNA sensors in the interferon stimulatory DNA (ISD) pathway
Authors: Gray Elizabeth , Stetson Daniel 
Published: May 2016

Abstract
Detection of viral DNA and production of type I interferons (IFNs) are essential for antiviral immunity and immune responses against transformed cells; on the other hand, inappropriate immune responses to self DNA result in autoimmunity. Intracellular DNA sensing activates the STING-dependent IFN stimulatory DNA (ISD) pathway. Multiple DNA sensors have been proposed to activate the ISD pathway, including cyclic GMP-AMP synthase (cGAS) and a family of DNA binding receptors called the AIM2-like receptors (ALRs). Analysis of cGAS-deficient mice has revealed that cGAS is required for the IFN response to transfected DNA ligands, DNA viruses, and retroviruses. In contrast, while multiple studies have suggested that ALRs promote an optimal IFN response to various DNA pathogens, others have found that the IFN response is intact following ALR knockdown. Thus, while cGAS has clearly emerged as a key DNA sensor in the ISD pathway, the function of the ALRs remains unclear.
To define the relative contributions of the ALRs and cGAS to the ISD pathway, we generated mice lacking all thirteen ALR genes and cGAS-deficient mice. In addition, we have used CRISPR gene targeting to disrupt cGAS and all four human ALRs in human cells. Analysis of IFN induction following transfection of DNA ligands or DNA virus infection has revealed that cGAS is absolutely required for activation of the ISD pathway in both mouse and human cells, consistent with recent studies. In contrast, the IFN response to transfected DNA ligands and infection with a variety of DNA viruses is intact in ALR-deficient cells, suggesting that the ALRs may be dispensable for activation of the ISD pathway. We are currently exploring potential alternative functions of the ALR family of DNA binding receptors.
Citation Format: Elizabeth Gray, Daniel Stetson. Functional analysis of DNA sensors in the interferon stimulatory DNA (ISD) pathway. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr A167.
Abstract A171: Long-term episomal gene transfer for safe engineering of T cells for adoptive cell therapy of cancer
Authors: Jin Chuan , Ramachandran Mohanraj , Fotaki Grammatiki , Nilsson Berith , Essand Magnus , Yu Di 
Published: May 2016

Abstract
Success in T-cell therapy of cancer is currently relying on long-term gene expression owing to retrovirus/lentivirus (RV/LV) integration. However, uncontrolled RV/LV integration in host cell genomes has the potential risk of causing insertional mutagenesis. Herein, we describe a novel episomal and long-term cell engineering method using non-integrating lentiviral (NILV) vector containing a scaffold matrix attachment region (S/MAR) element for either over-expression or down-regulation of genes. T-cells engineered with a NILV-S/MAR(CD19CAR) vector have similar levels of CAR expression as T-cells engineered with an integrating LV vector, even after numerous rounds of cell division. NILV-S/MAR-engineered CD19CAR-T-cells exhibited similar cytotoxic capacity upon CD19+ target cells recognition as LV-engineered T-cells. We propose that NILV-S/MAR vectors are superior to current options for enabling long-term gene expression without the risk of insertional mutagenesis.
Citation Format: Chuan Jin, Mohanraj Ramachandran, Grammatiki Fotaki, Berith Nilsson, Magnus Essand, Di Yu. Long-term episomal gene transfer for safe engineering of T cells for adoptive cell therapy of cancer. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr A171.
Abstract A183: Molecular elucidation of the CBM complex in NF-kappaB activation by using single molecule imaging and structural studies
Authors: David Liron , Wu Hao 
Published: May 2016

Abstract
NF-kB family proteins are evolutionarily conserved master regulators of immune and inflammatory responses. NF-kB signaling has a crucial role in regulating the activation, proliferation and effectors functions of lymphocytes in adaptive immune responses. The CARMA1/Bcl10/MALT1 (CBM) complex is the central mediator of TCR and BCR induced NF-kB activation in lymphocytes. Mutations, chromosomal translocations and over-expressions of CBM component proteins have been shown to directly lead to non-Hodgkin's lymphomas. Elucidating the molecular basis of assembly and activation of the CBM complex could provide a platform for mechanistic understandings of the associated lymphomas and potential therapeutic target identification. Our research goals are to investigate the CBM mechanism in the NF-kB activation pathway by single molecule imaging and structural studies on the CARMA1/Bcl10, BCl10/MALT1 and CBM complex by combining electron microscopy and X-ray crystallography. We have succeeded in purifying the CARMA1/Bcl10/MALT1 complex and shown by negative staining EM that the CBM complexes form filamentous structures as well as BCl10 only. In vitro, polymerization assay indicated that CARMA1 nucleates Bcl10 filament assembly, which could promote downstream MALT1 activation. Based on the 3D map from negative stained electron microscopy and high-resolution individual structures of CARMA1/Bcl10 CARD domains, we reconstituted a structure model of CARMA1/Bcl10 filament. Single molecule imaging enables us to track after the filament formation of labeled BCl10 filaments and the nucleation of BCl10 by labeled CARMA1 and determine the filaments formation rates in vitro supported by kinetic studies. In addition, we could determine that polymerization BCl10 has polarity and the filament growth is only at one end. Moreover, Real time Super Resolution Microscopy (STORM) measurements showed a surprising funding that CARMA1(8-302) is segmented along the filaments and incorporated within BCl10 filaments. At the moment, we are pursuing the determination of cryo-EM structures of BCl10 and BCl10/ MALT1 complex. At the moment, we are processing BCl10 and BCl10/ MALT1 complex data sets that were collected with a K2 detector and by using Titan cryoEM microscope. BCl10 (1-205) structure was solved to a 6Å and the data is currently being further improved.
Citation Format: Liron David, Hao Wu. Molecular elucidation of the CBM complex in NF-kappaB activation by using single molecule imaging and structural studies. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr A183.
Abstract B007: Targeting the ubiquitin signaling system for cancer immunotherapy
Authors: Kumar Suresh , Wang Liqing , Wu Jian , Wang Feng , Agarwal Saket , Kodrasov Matthew , Hancock Wayne , Mattern Michael 
Published: May 2016

Abstract
Studies have been performed to demonstrate that effectors of enzymes of the ubiquitin proteasome pathway associated with T cell activation are able to impair tumor survival by abrogating the immune evasion mechanism. Immune evasion is a collective term for the various strategies employed by tumors to suppress the host immune system's ability to recognize and destroy cancer cells. Significant advances in the understanding of the mechanisms of cancer immune evasion have led to the successful development of biologic immunotherapies that showed clinical efficacy against hematological as well as solid tumors. These include monoclonal antibodies, allogeneic hematopoietic stem cell transplantation, vaccination, cytokines, T cell checkpoint blockade and adoptive transfer of engineered T cells. Owing to the multifaceted nature of cancer immune evasion, however, several different approaches will likely be necessary for effective therapeutic management. We have adopted a dual targeting approach focused on the ubiquitin proteasome pathway to develop novel small molecule cancer immunotherapies. Using the UbiProTM discovery platform, we have identified inhibitors of a deubiquitylase (DUB) that is highly expressed in regulatory T cells (Tregs) and plays a critical role in promoting Treg functions. These inhibitors are shown to suppress Treg functions and promote T-effector cell function ex vivo and in vivo. In addition, we have identified inhibitors of an E3 ubiquitin ligase that negatively regulates T-effector cell function. These inhibitors are shown to activate T-cells and NK cell functions in vitro. A combination of such inhibitors should provide powerful anti-cancer immunotherapy.
Citation Format: Suresh Kumar, Liqing Wang, Jian Wu, Feng Wang, Saket Agarwal, Matthew Kodrasov, Wayne Hancock, Michael Mattern. Targeting the ubiquitin signaling system for cancer immunotherapy. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr B007.
Abstract B013: A soluble form of CD80 enhances anti-tumor immunity by inhibiting PDL1 immune suppression and does not suppress via CTLA-4
Authors: Horn Lucas , Clements Virginia , Ostrand-Rosenberg Suzanne 
Published: May 2016

Abstract
Tumor cells employ various methods of immune suppression to overcome anti-tumor immunity. One such method is that of the integral membrane protein programmed death ligand-1 (PDL1), which triggers apoptotic death or anergy upon binding programmed death-1 (PD1) on T cells. Treatment of PDL1+ tumor cells with a soluble form of the costimulatory molecule CD80 (CD80-Fc) prevented PDL1-mediated immune suppression by binding PDL1 and blocking interaction with PD1, thus restoring T cell activation. Additionally, CD80-Fc maintained activation of T cells in vitro more effectively than either PD1 or PDL1 antagonist monoclonal antibodies. Because CTLA-4 is also a receptor for CD80 and CD80-Fc has the potential to bind and deliver inhibitory signals into T cells via CTLA-4, it is important to assess CD80-Fc and CTLA-4 interactions. Healthy donor human PBMC stimulated with PHA for three days express CD28, PDL1, and CTLA-4 at the cell surface. To determine which of these receptors CD80-Fc binds to, we have blocked subsets of the receptors using very high concentrations of specific antibodies, and monitored CD80-Fc binding by flow cytometry. CD80-Fc binds to activated T cells blocked for CD28 and PDL1, PDL1 and CTLA-4, or CTLA-4 and CD28, and did not bind when all three receptors were blocked. These findings indicate that CD80-Fc binds to CTLA-4. However, inclusion of CTLA-4 antagonist antibodies L3D10 or Ipilimumab in co-cultures of human PBMC and PDL1+ C8161 human melanoma cells did not increase T cell production of IFNγ, suggesting that CD80-Fc is not suppressing through CTLA-4. Historically, CTLA-4 has been considered as a negative regulator of T cell function through its ability to deliver suppressive signals to T cells. Recent re-evaluations of CD80-CTLA-4 interactions suggest that CTLA-4 inhibits T cell function not by delivering intracellular signals, but by serving as a decoy receptor for CD80. Our results support this alternative functional mechanism and are consistent with the concept that CD80-Fc maintains T cell activation by saturating CTLA-4 receptors while simultaneously blocking PDL1 suppression and providing CD28 costimulation.
Citation Format: Lucas Horn, Virginia Clements, Suzanne Ostrand-Rosenberg. A soluble form of CD80 enhances anti-tumor immunity by inhibiting PDL1 immune suppression and does not suppress via CTLA-4. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr B013.
Abstract B042: Regulation of Lck activity by a cryptic phosphosite
Authors: Courtney Adam H. , Sjolin-Goodfellow Hanna E. , Ji Qinqin , Kadlecek Theresa A. , Salomon Arthur R. , Weiss Arthur 
Published: May 2016

Abstract
Src family kinases (SFKs) are initiators of receptor-mediated signaling events, enabling cells to perceive and interact with their environment. For immune cells SFKs are especially crucial because they couple antigen recognition to intracellular signaling pathways. In T cells, the SFK Lck phosphorylates the T cell antigen receptor (TCR) complex upon antigen encounter. Because Lck phosphorylates the TCR complex, its activity sets a critical threshold for T cell activation; yet how Lck activity is regulated in resting or stimulated cells is poorly understood. Through quantitative mass spectrometry (SILAC), we recently identified a cryptic Lck phosphosite (Y192) as sensitive to inhibition of the effector kinase Zap70. Because Zap70 is an Lck substrate, and dramatic reduction in phosphorylation of Y192 occurred upon Zap70 inhibition, we reasoned this site might function to regulate Lck in response to changes in Zap70 activity. To test this hypothesis we reconstituted Lck-deficient Jurkat T cells with Lck Y192 variants. Mutation of Y192 reveals that this site has a profound impact on Lck activity. Cells reconstituted with Y192E or Y192A show a marked reduction in Lck activity, characterized by hyperphosphorylation on Lck's inhibitory C-terminus (Y505) and a reduction in Lck autophosphorylation within the activation loop (Y394). Consistent with a defect in Lck activity, cells that express Lck Y192E/A variants, when assessed for hallmarks of T cell activation, reveal striking defects in TCR signaling. Interestingly, these defects are reminiscent of CD45-deficient T cells. Preliminary findings suggest that mutation of Y192 disrupts the ability of the phosphatase CD45 to dephosphorylate Lck's inhibitory C-terminus (Y505). Because of the profound effect that Y192 modification exerts on Lck activity, and therefore TCR signaling, we believe that phosphorylation of Y192 comprises a Zap70-dependent negative feedback mechanism that tunes Lck activity. Such a mechanism predicts that increases in Zap70 activity cause phosphorylation of Y192 within Lck's SH2 domain, favouring Lck inactivation by preventing CD45-mediated dephosphorylation of the inhibitory C-terminus.
Citation Format: Adam H. Courtney, Hanna E. Sjolin-Goodfellow, Qinqin Ji, Theresa A. Kadlecek, Arthur R. Salomon, Arthur Weiss. Regulation of Lck activity by a cryptic phosphosite. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr B042.
Abstract B058: Expansion and activation of CD103+ DC progenitors at the tumor site promote T cell accumulation in melanoma lesions and transform clinical response to BRAF and PD-L1 blockade
Authors: Salmon Hélène , Idoyaga Juliana , Rahman Adeeb , Palucka Anna Karolina , Bhardwaj Nina , Ginhoux Florent , Merad Miriam 
Published: May 2016

Abstract
A high number of melanoma lesions develop resistance to BRAF blockade or fail to respond to checkpoint inhibition therapy. Here we explored whether modulation of intratumoral APC can increase responses to BRAF or PD-L1 blockade in Braf-mutant and B16 melanoma. In both models, CD103+ DC were the only APC that transported intact antigens to the lymph nodes and primed tumor-specific CD8+ T cells. CD103+ DC expressed high PD-L1 levels, however PD-L1 or BRAF blockade led to partial response and minimal accumulation of intratumoral T cells. Strikingly, systemic Flt3L followed by intratumoral poly I:C injections expanded and activated CD103+ DC progenitors in the tumor mass, leading to dramatic expansion of intratumoral CD8+ T cells enhancing responses to BRAF and PD-L1 blockade and protecting mice from tumor rechallenge. Thus the paucity of activated CD103+ DC in tumors limit checkpoint blockade efficacy and Flt3L/poly I:C combination can significantly enhance clinical response to checkpoint and BRAF blockade.
Citation Format: Hélène Salmon, Juliana Idoyaga, Adeeb Rahman, Anna Karolina Palucka, Nina Bhardwaj, Florent Ginhoux, Miriam Merad. Expansion and activation of CD103+ DC progenitors at the tumor site promote T cell accumulation in melanoma lesions and transform clinical response to BRAF and PD-L1 blockade. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr B058.