bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B028: Transcriptional and epigenetic signatures of ex vivo propagated three distinct TCR Vδ1, TCR Vδ2 and TCR Vδ3 cell subtypes with broad specificity for malignancies
Authors: Maiti Sourindra , Deniger Drew , Dai Jianliang , Cooper Laurence 
Published: May 2016

Abstract
Functionally pleiotropic human γδ T cells are a unique set of immune cells that exhibit qualities of both innate and adaptive immune responses. In contrast to αβ T cells, γδ T cells recognize their ligands independent of MHC and are infrequent (1%–5% of T cells) in peripheral blood. Studies have shown that γδ T cells exhibit endogenous cytotoxicity towards tumor cells by directly recognizing a diverse array of Tumor Associated Antigen (TAA) and have the ability to present TAA to elicit an antitumor response. This broad recognition of antitumor activity is achieved because these cells express a diverse TCR γδ repertoire (combination of Vδ1, Vδ2, or Vδ3 with one of fourteen Vγ chains). Because of their characteristics γδ T cells are attractive targets for clinical manipulation and tumor immunotherapy. To obtain clinically significant numbers of cells for immunotherapy current ex vivo γδ T cells expansion protocol uses Zoledronic acid, an aminobisphosphonate that results only in selective propagation of Vγ9Vδ2. These cells however, showed clinical response against both solid and hematologic tumors. We have previously shown a novel ex vivo expansion protocol using artificial antigen presenting cells (aAPC), IL2 and IL21 assist aAPC in activating and expanding polyclonal γδ T-cells (Vδ1, Vδ2 and Vδ1neg Vδ2neg T cell subtypes) to clinically significant numbers. These expanded cell subsets secrete proinflammatory cytokines, lysed a broad range of malignancies and improved survival in ovarian cancer xenograft model. To better define the role of the subsets and their application in immunotherapy here we present high-resolution transcriptome, microRNA and secreted cytokine-chemokine signatures of ex vivo expanded subsets. Our data provide an atlas of transcriptional, epigenetic and secretome of three defined subsets, and subset-specific signatures. The data presented here will have a broader impact in understanding the immunobiology of γδ T cell subsets and facilitate improving the human application of these cells in cancer immunotherapy.
Citation Format: Sourindra Maiti, Drew Deniger, Jianliang Dai, Laurence Cooper. Transcriptional and epigenetic signatures of ex vivo propagated three distinct TCR Vδ1, TCR Vδ2 and TCR Vδ3 cell subtypes with broad specificity for malignancies. [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 B028.
Abstract B031: Heat-inactivated modified vaccinia virus ankara induces type I IFN and antitumor immunity via the cytosolic DNA-sensing pathway
Authors: Dai Peihong , Wang Weiyi , Serna-Tamayo Cristian , Zamarin Dimitriy , Shuman Stewart , Merghoub Taha , Wolchok Jedd D. , Deng Liang 
Published: May 2016

Abstract
Type I interferon (IFN), well known for its antiviral activity, is a critical component of cancer immune surveillance through its direct actions on cancer cells as well as on tumor microenvironment. Advanced melanoma remains a therapeutic challenge despite recent progress in targeted therapy and immunotherapy. Novel approaches are needed to alter the tumor immune suppressive microenvironment and to facilitate the recognition of tumor antigens that leads to antitumor immunity. Poxviruses are cytosolic DNA viruses that have been investigated as oncolytic and immunotherapeutic agents. We recently reported that the highly attenuated modified vaccinia virus Ankara (MVA), a safe vaccine for smallpox, triggers type I IFN production in conventional dendritic cells (cDCs) via the cytosolic DNA sensor cGAS and its adaptor STING, and that it requires transcription factors IRF3 and IRF7. Here we show that infection of cDCs with heat-inactivated MVA leads to higher levels of IFN induction than MVA. This induction is also mediated by the cytosolic DNA-sensing pathway cGAS/STING/IRF3/IRF7. In addition, we found that intratumoral injection of Heat-MVA caused tumor eradication in a murine B16 melanoma model as well as the generation of adaptive anti-tumor immunity. Furthermore, Heat-MVA-induced anti-tumor therapy is less effective in STING, IRF7, or Batf3-deficient mice than in wild-type mice, indicating that both the innate immune-sensing pathway and CD8α+DCs are essential for Heat-MVA-based immunotherapy. Lastly, the combination of intratumoral delivery of Heat-MVA with systemic delivery of anti-CTLA-4, PD-1 or PD-L1 antibodies achieved enhanced efficacy in tumor eradication and survival than Heat-MVA alone. Our results have strong implications for the development of poxvirus-based cancer immunotherapeutics as well novel strategies to overcome resistance to immune checkpoint blockade therapy.
Citation Format: Peihong Dai, Weiyi Wang, Cristian Serna-Tamayo, Dimitriy Zamarin, Stewart Shuman, Taha Merghoub, Jedd D. Wolchok, Liang Deng. Heat-inactivated modified vaccinia virus ankara induces type I IFN and antitumor immunity via the cytosolic DNA-sensing 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 B031.
Abstract B036: Monoclonal antibodies against GARP/TGF-β1 complexes inhibit the immunosuppressive activity of human regulatory T cells in vivo
Authors: Liénart Stéphanie , Cuende Julia , Saunders Michael , Woning Bas van der , Haard Hans De , Coulie Pierre G. , Lucas Sophie 
Published: May 2016

Abstract
Regulatory T lymphocytes (Tregs) are essential to prevent auto-immunity, but excessive Treg function contributes to cancer progression by inhibiting anti-tumor immune responses. Tregs exert contact-dependent inhibition of immune cells through the production of active TGF-β1. On the Treg cell surface, TGF-β1 is in an inactive form bound to membrane protein GARP and then activated by an unknown mechanism. Here, we demonstrate that GARP is involved in this activation mechanism. Two anti-GARP monoclonal antibodies were generated that block the production of active TGF-β1 by human Tregs. These antibodies recognize a conformational epitope that requires amino-acids GARP137-139 within GARP/TGF-β1 complexes. A variety of antibodies recognizing other GARP epitopes did not block active TGF-β1 production by Tregs. In a model of xenogeneic graft-versus-host disease in NSG mice, the blocking antibodies inhibited the immunosuppressive activity of human Tregs. These antibodies may serve as therapeutic tools to boost immune responses to infection or cancer, via a mechanism of action distinct from that of currently available immuno-modulatory antibodies. Used alone or in combination with tumor vaccines or antibodies targeting the CTLA4 or PD1/PD-L1 pathways, blocking anti-GARP antibodies may improve the efficiency of cancer immunotherapy.
Citation Format: Stéphanie Liénart, Julia Cuende, Michael Saunders, Bas van der Woning, Hans De Haard, Pierre G. Coulie, Sophie Lucas. Monoclonal antibodies against GARP/TGF-β1 complexes inhibit the immunosuppressive activity of human regulatory T cells in vivo. [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 B036.
Abstract B046: Mechanisms of T lymphocyte activation revealed by super-resolution microscopy
Authors: Traver Maria , Campanello Leonard , Paul Suman , Losert Wolfgang , Shroff Hari , Schaefer Brian 
Published: May 2016

Abstract
Tight regulatory control of lymphocyte activation is necessary to avoid the deleterious consequences of an uncontrolled immune response. A complicated web of up-regulatory and down-regulatory processes governs a key activation pathway in lymphocytes, the antigen-receptor-to-NF-κB pathway; however, the complex interplay between positive and negative regulation of this pathway remains poorly understood. We have utilized cutting-edge super-resolution imaging technologies to examine the spatial and temporal organization of the POLKADOTS signalosome, which is inducibly formed in response to antigen stimulation of T lymphocytes. Our preliminary results suggest that this filamentous signalosome is divided into two distinct subregions: an activation domain which recruits signal transduction elements, and a downregulation domain which promotes macroautophagic degradation of the signalosome. Fixed and live cell imaging of the activation process indicates that POLKADOTS filaments converge on the microtubule-organizing center as the core filament protein Bcl10 is progressively degraded by autophagosomes. Furthermore, following Bcl10 degradation, the POLKADOTS components Malt1 and phospho-IKK are transferred to a peri-nuclear aggresomal structure. Surprisingly, our data suggest these aggresomal accumulations continue to promote NF-κB nuclear localization and T cell activation. Together, these results provide new insights into the complex regulatory processes which govern T lymphocyte activation, and for the first time suggest a signaling function for aggresomes.
Citation Format: Maria Traver, Leonard Campanello, Suman Paul, Wolfgang Losert, Hari Shroff, Brian Schaefer. Mechanisms of T lymphocyte activation revealed by super-resolution microscopy. [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 B046.
Abstract B048: The MHC class II transactivator CIITA inhibits the persistent activation of NF-kB by Human T cell Lymphotropic Virus type-1 Tax-1 oncoprotein
Authors: Forlani Greta , Abdallah Rawan , Accolla Roberto S. , Tosi Giovanna 
Published: May 2016

Abstract
Human T cell Lymphotropic Virus type-1 (HTLV-1) Tax-1 protein, a key mediator of HTLV-1-induced T-cell transformation, deregulates diverse cell-signalling pathways. Among them, the NF-kB pathway is constitutively activated by Tax-1, which binds to NF-kB family members and activates the IkB-kinase (IKK). Upon phosphorylation-dependent degradation of IkB, NF-kB migrates into the nucleus and mediates Tax-1-stimulated gene expression. We show that CIITA, the transcriptional regulator of Major Histocompatibility Complex Class II genes, inhibits the activation of the canonical NF-kB pathway by Tax-1 and map the region mediating this effect. CIITA affects the subcellular localization of Tax-1, which is mostly retained in the cytoplasm, and this correlates with an impaired migration of RelA into the nucleus. Cytoplasmic and nuclear CIITA mutants reveal that CIITA exploits different strategies to suppress Tax-1-mediated NF-kB activation in both subcellular compartments. CIITA interacts with Tax-1 without preventing Tax-1 binding to both IKKg and RelA. Nevertheless, CIITA affects Tax-1-induced IKK activity causing the retention of the inactive p50/RelA/IkB complex in the cytoplasm. Nuclear CIITA associates with Tax-1/RelA in nuclear bodies blocking the activation of NF-kB-responsive genes by Tax-1. Thus, CIITA inhibits critical cytoplasmic and nuclear steps of Tax-1-mediated NF-kB activation. These results, together with our previous finding that CIITA acts as a restriction factor inhibiting Tax-1-promoted HTLV-1 gene expression and replication, indicate that CIITA is a versatile molecule that might also counteract Tax-1 transforming activity. Unveiling the molecular basis of CIITA-mediated inhibition of Tax-1 functions may be important in defining new strategies to control HTLV-1 spreading and oncogenic potential.
Citation Format: Greta Forlani, Rawan Abdallah, Roberto S. Accolla, Giovanna Tosi. The MHC class II transactivator CIITA inhibits the persistent activation of NF-kB by Human T cell Lymphotropic Virus type-1 Tax-1 oncoprotein. [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 B048.
Abstract B059: Slow maturation of early phagosomes promotes a TAP independent antigen cross-presentation pathway
Authors: Sengupta Debrup , Cresswell Peter 
Published: May 2016

Abstract
Early phagocytic compartments play a role in protein sorting, signaling and neutralizing pathogens. In addition, certain subsets of dendritic cells (DCs) load peptides derived from exogenous antigens on to MHC class-I molecules in early phagosomes. This process plays a key role in antigen cross-presentation, a process particularly important in the activation of naïve CD8+ T-cells when it is known as cross-priming and is essential for mounting an immune response against tumor and viral antigens. The functional properties of early phagosomes that facilitate cross-presentation remain unclear. Here we show that the expression of Rab GTPase mutants (Rab5CA, Rab7DN and Rab22CA) that impair maturation of phagosomes enhance antigen cross-presentation efficiency of DCs as well as an engineered derivative of 293T cells capable of cross-presentation. Enhanced antigen cross-presentation observed upon expression of the Rab5CA, Rab7DN and Rab22CA mutants remains dependent on proteasome activity. However, expression of the mutants renders cross-presentation independent of the activity of Transporter associated with antigenic peptide (TAP). These findings taken together reveal a novel TAP independent but proteasome dependent mechanism of MHC class I-restricted antigen processing and peptide loading that is facilitated by slow maturation of endocytic compartments.
Citation Format: Debrup Sengupta, Peter Cresswell. Slow maturation of early phagosomes promotes a TAP independent antigen cross-presentation 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 B059.
Abstract B069: Systemic alterations in T cell subpopulations of breast cancer patients
Authors: Pinho Mariana Pereira , Barbuto José Alexandre Marzagão 
Published: May 2016

Abstract
Breast cancer patients have immune system functional deviations, that affect immune cells that infiltrate the tumor, but also cells from the blood compartment, even in the absence of a metastatic disease. Blood monocytes of these patients, for example, have impaired ability to differentiate into dendritic cells. Little is known, however, about systemic alterations in T cells from these patients. To address this issue, we evaluated T cell populations in peripheral blood of cancer patients, comparing it to those of healthy donors. For this, peripheral blood mononuclear cells (PBMCs) were isolated by Ficoll-Paque centrifugation, stained with antibodies to different T cell markers, and evaluated by flow cytometry. Patients had lower CD4:CD8 ratio then healthy donors (Healthy: 2.91±0.31; Cancer: 2.06±0.32; n=10; p=0.04). There was a positive correlation between the histological grade of the tumor and the CD4:CD8 ratio, where those with the lower grade had the lower CD4:CD8 ratio (r2=0.5679; p=0.03). Regarding CD4+ T cells, cancer patients had the same percentage of effector (CD45RA+CCR7-) and central memory (CD45RA-CCR7+) CD4+ T cells, but significantly lower naïve (CD45RA+CCR7+) CD4+ T cells (Healthy: 30.82±5.94, n=8; Cancer: 14.21±3.46, n=10; p=0.02) and a tendency to have higher effector memory (CD45RA-CCR7-) CD4+ T cells (Healthy: 35.13±5.54, n=8; Cancer: 48.64±4.52, n=10; p=0.08). When comparing CD8+ T cells, patients also had significantly lower naïve CD8+ T cells (Healthy: 42.74±6.97, n=8; Cancer: 19.16±3.42, n=10; p=0.005) and higher effector memory CD8+ T cells (Healthy: 29.69±5.35, n=8; Cancer: 45.37±5.15, n=10; p=0.05). Interestingly, cancer patients seemed to have higher percentage of effector CD8+ T cells than healthy patients (Healthy: 19.54±5.30, n=8; Cancer: 30.30±5.49, n=10; p=0.18). No difference in the expression of the IL-2 high affinity receptor (CD25) was observed between individuals with or without breast cancer. In conclusion, breast cancer patients had significant alterations in the percentage of the different peripheral blood T cell populations, suggesting that these may affect their ability to respond to the tumor, but also to other antigens.
Financial Support: FAPESP (2014/25988-1).
Citation Format: Mariana Pereira Pinho, José Alexandre Marzagão Barbuto. Systemic alterations in T cell subpopulations of breast cancer patients. [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 B069.
Abstract B081: Tissue repair function of regulatory T cells during infection and cancer progression
Authors: Hu Wei , Arpaia Nicholas , Bos Paula D. , Green Jesse , Rudensky Alexander 
Published: May 2016

Abstract
Regulatory T (Treg) cells dampen immune responses to avoid excessive, deleterious inflammation in the context of autoimmunity, allergic reactions, and infection. Treg cells also impede anti-tumor immunity. Therefore, modulation of Treg cell activity is of great therapeutic potential for treating many debilitating inflammatory diseases and cancer. Recent studies have implicated a specialized tissue-resident Treg subset in limiting metabolic inflammation in the adipose tissue and in promoting repair of muscle injury. These Treg cells exhibit a unique transcriptional signature represented by high expression of the EGF family member amphiregulin (Areg), suggesting an additional role for Treg cells in tissue maintenance and remodeling. Whether Treg cells regulate tissue maintenance in broader settings, such as during infection and cancer progression, however, remains unknown. In the present study, we observed an Areg+ Treg subset in lung-infiltrating Treg cells following influenza infection. Selective ablation of Areg in Treg cells led to severe impairment of lung function and tissue damage without evident change in viral burden or antiviral response, indicating that the tissue maintenance function of Treg cells is distinct from their immune regulatory roles. Remarkably, we found that tumor infiltrating Treg cells highly expressed Areg. Since Areg is known to exert pleiotropic oncogenic activities, Areg production by Treg cells may be crucial for establishing the tumor microenvironment. Future studies will focus on: (1) Further examine the role for Areg+ Treg cells in tissue remodeling, during infection as well as cancer progression; (2) Characterize the Areg+ Treg cell subset; (3) Define the differentiation pathway of the Areg+ Treg cells. These studies will improve our understanding of both the immune and non-immune functions of Treg cells, and could provide new strategies for selectively targeting particular aspects of Treg cell function therapeutically in the treatment and control of inflammatory diseases and cancer progression.
Note:This abstract was not presented at the conference.
Citation Format: Wei Hu, Nicholas Arpaia, Paula D. Bos, Jesse Green, Alexander Rudensky. Tissue repair function of regulatory T cells during infection and cancer progression. [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 B081.
Abstract B083: Human tumor-based identification of immune checkpoint targets
Authors: McQuade Thomas , Wang Yanyan , Doty Daniel , Amirina Najmia , Vadde Sri , Chamarthi Hareesh , Nguyen Cokey , Ranganath Sheila , Watkins-Yoon Jennifer 
Published: May 2016

Abstract
The recent advances in immune checkpoint (IC) blockade highlight the need to develop novel IC drug combinations. However, it remains challenging to determine which IC should be targeted in a particular indication. Enumeral uses an innovative approach to identify relevant ICs for which blockade could restore immune cell function. We use our proprietary single cell technology to assess the tumor microenvironment of human tissues and to elucidate the appropriate IC to antagonize on tumor infiltrating lymphocytes. Once appropriate IC targets are found in human tumors, monoclonal antibodies are generated and validated in vitro and ex-vivo. We tested combinations of monoclonal antibodies against ICs at the single cell level in tumor samples for reversal of immune cell exhaustion. Several anti-PD-1 and anti-TIM-3 lead candidates have been characterized in preparation for clinical studies using this strategy.
Citation Format: Thomas McQuade, Yanyan Wang, Daniel Doty, Najmia Amirina, Sri Vadde, Hareesh Chamarthi, Cokey Nguyen, Sheila Ranganath, Jennifer Watkins-Yoon. Human tumor-based identification of immune checkpoint targets. [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 B083.
Abstract B088: Can the pro-tumorigenic activity of Th17 cells be a therapeutic opportunity?
Authors: Gagliani Nicola , Vasely Carolina Amezcua , Xu Hao , Huber Samuel , Flavell Richard 
Published: May 2016

Abstract
Chronic inflammation in the intestine increases the risk of developing colorectal cancer. This becomes evident in patients with inflammatory bowel disease (IBD), such as ulcerative colitis and Crohn's patients, who indeed have a higher probability of developing colitis-associated cancers. The main aim of the project is to control colorectal cancer development by targeting Th17 cells, a subset of CD4 T cells, which are fundamental in promoting chronic intestinal inflammation when they escape the physiological controls. By the combination of different cutting edges technologies, including fate-cytokine reporter mouse models and RNA seq., we found that formerly pro-inflammatory Th17 cells can convert into regulatory T cells (Tregs) and acquire a strong IL-10-mediated anti-inflammatory function (Gagliani N. et al.; Nature; 2015). Moreover we proved that Th17 cells infiltrate the intestinal tumors and produce IL-22, a cytokine known to be pro-tumorigenic (Unpublished data). Considering that (i) Th17 cells infiltrate and support tumor development, (ii) could be converted into Tregs and (iii) that IL-10 production it has been shown to have anti-tumorigenic effect, we are about to test whether by forcing the conversion of pro-tumrogienc Th17 into anti-tumorigenic regulatory T cells, it is possible to reduce intestinal tumor development in preclinical mouse models.
Citation Format: Nicola Gagliani, Carolina Amezcua Vasely, Hao Xu, Samuel Huber, Richard Flavell. Can the pro-tumorigenic activity of Th17 cells be a therapeutic opportunity? [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 B088.