bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A016: Multipotency of a CD40L-expressing recombinant vaccinia virus
Authors: Trella Emanuele 
Published: November 2016

Abstract
Vaccinia Virus (VV) is a viral vector used in pre-clinical and clinical studies of active cancer immunotherapeutic strategies. CD40 receptor is expressed on a broad range of immune cells. Furthermore, CD40 expression has been reported also in nearly all B-cell malignancies and solid tumors of different origins. Interestingly, CD40 ligation might result in different biological responses depending on the cell types and to the strength of CD40 ligand (CD40L; CD154)-mediated stimulation of CD40 receptor. Based on this background, we have generated a replication incompetent CD40 ligand-expressing recombinant vaccinia virus (rVV40L) and we have investigated its antitumor activity. Notably, rVV40L-infection resulted in an improvement of (i) the antigen presenting capacity of CD40+ nonprofessional CD14+ monocytes leading (ii) to the rapid expansion and differentiation of human naïve CD8+ T cells into central memory T cells (TCM) specific for tumor associated antigens (TAAs), (ii) the induction of apoptotic effects on CD40+ established tumor cell lines of different origin and (iii) the antitumor activity, TNF-mediated, of macrophages. Collectively, these data indicate that rVV40L can be considered a successful viral vector for cancer immunotherapy according to its multiple mechanisms of action.
Citation Format: Emanuele Trella. Multipotency of a CD40L-expressing recombinant vaccinia virus [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 A016.
Abstract A044: Immunological effects of a novel RNA-based adjuvant in liver cancer patients
Authors: Circelli Luisa , Petrizzo Annacarmen , Tagliamonte Maria , Heidenreich Regina , Tornesello Maria Lina , Buonaguro Franco M. , Buonaguro Luigi 
Published: November 2016

Abstract
Evaluation of detailed biological effects of adjuvants on immune cells has been assessed in a limited number of studies performed only on samples derived from healthy individuals. No data are available on samples derived from cancer patients who may have a severe immune impairment. A novel RNA-based adjuvant (RNAdjuvant® developed by CureVac) is made of a synthetic single stranded RNA molecule combined with a polymeric carrier. It is known to interact with toll-like receptors (TLRs) 7. The effects of RNAdjuvant® on PBMCs of liver cancer patients was assessed in an ex vivo setting, using a multiparametric approach to analyze network dynamics of early human immune responses. PBMCs were obtained from 8 healthy volunteers and 17 HCC patients enrolled in the present study. After treatment in culture, the effects of RNAdjuvant® were assessed by evaluation of CD80, CD86 and HLA-DR expression, pattern of cytokine production as well as gene expression profile. Moreover, the downstream effect on CD4+ T cell phenotyping was evaluated. The TLR4 ligand LPS was used as comparison. Treatment with RNAdjuvant® showed comparable effects on PBMCs of both HCC and healthy subjects, as shown by all the evaluated parameters. CD80, CD86 and HLA-DR expression was found upregulated in circulating dendritic cells, which promoted a CD4+ T cell differentiation towards an effector phenotype. A mixed Th1/Th2 cytokine pattern was induced in PBMCs, although a more predominant production of TNFα and IFNγ was observed in HCC patients vs. healthy controls. The cytokine profile was further confirmed by gene transcriptional analysis, which showed up-regulation of several genes involved in innate and adaptive immune-related pathways.
Citation Format: Luisa Circelli, Annacarmen Petrizzo, Maria Tagliamonte, Regina Heidenreich, Maria Lina Tornesello, Franco M. Buonaguro, Luigi Buonaguro. Immunological effects of a novel RNA-based adjuvant in liver cancer 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 A044.
Abstract A045: Inhibition of tumor growth by combination of metronomic chemotherapy and checkpoint inhibitor with a cancer vaccine
Authors: Tagliamonte Maria , Petrizzo Annacarmen , Mauriello Angela , Luciano Antonio , Rea Domenica , Barbieri Antonio , Arra Claudio , Maiolino Piera , Tornesello Maria Lina , Ciliberto Gennaro , Buonaguro Franco M. , Buonaguro Luigi 
Published: November 2016

Abstract
The efficacy of cancer immunotherapies can be significantly limited by the immune suppressive soluble factors and cell types characterizing the tumor microenvironment. Strategies combining anti-immune suppressive therapies and cancer vaccines need to be evaluated. In the present study, a novel combinatorial strategy was assessed in a mouse model using an aggressive therapeutic setting based on sub-cutaneous ectopic implantation of B16 melanoma cells. The anti-immune suppressive therapy included a novel mix of chemotherapy agents, administered in a metronomic fashion (MCT), and an anti-PD-1 checkpoint inhibitor (CI). The vaccine (VAC) was a multi-peptide cocktail, including melanoma-specific tumor-associated antigens. The newly designed strategy was shown to be safe, well tolerated and highly effective. Animals treated with MCT or CI showed a remarkable delay in tumor growth and prolonged survival as compared to control group. Such effect was significantly enhanced by the combination with the multi-peptide vaccine. In particular, the multi-pronged MCT+CI+VAC combination resulted in a remarkable inhibition of tumor growth in 5/6 animals. The anti-tumor effect was associated with a strong T cell immune response to vaccine peptides as well as significant intra-tumor T cell infiltration associated with reduction in Tregs. Overall, the results showed that the combination of anti-immune suppressive therapy and vaccine was able to strongly potentiate the anti-tumor effects. The described approach is highly promising to significantly enhance the anti-tumor effects induced by a therapeutic cancer vaccine.
Citation Format: Maria Tagliamonte, Annacarmen Petrizzo, Angela Mauriello, Antonio Luciano, Domenica Rea, Antonio Barbieri, Claudio Arra, Piera Maiolino, Maria Lina Tornesello, Gennaro Ciliberto, Franco M. Buonaguro, Luigi Buonaguro. Inhibition of tumor growth by combination of metronomic chemotherapy and checkpoint inhibitor with a cancer vaccine [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 A045.
Abstract A065: Oscillatory genes in lymphocyte retention and egress
Authors: Chen Hsin , Schmidt Timothy , Xu Ying , Lu Erick , Cyster Jason G. 
Published: November 2016

Abstract
The adaptive immune system attacks cancer cells by initiating immune responses in lymphoid organs and egressing of activated effector cells into circulation to reach the tumor. Several G protein-coupled receptors have been reported to recruit lymphocytes to the lymphoid organ or to promote exit. However, how these signals crosstalk to ensure efficient lymphocyte recruitment and transit is not well understood. To further define how cell transit through the lymphoid tissue is controlled, we designed two parallel RNAseq to identify novel regulators for lymphocyte transit. We compared the transcriptome of naïve B cells from the blood and peripheral lymph node. Also, by utilizing photoconvertible proteins, we isolated naive B cells that newly enter the lymphoid organ and those that have been dwelling for several hours. We identified multiple genes whose transcript levels were correlated with lymphoid dwelling time. One of the genes, KLF11, encoding a transcription factor, is expressed more highly in the blood than in the lymph node, and the expression decreases with the dwelling time in the lymphoid organ. Analysis of the KLF11 knock-out mouse identified strong lymphocyte transit and developmental defects, but we found the strong phenotypes segregated independently of the KLF11 knock-out allele. The phenotypes were the result of a mutated DOCK2 allele in the commercial B6 background. We have now generated a KLF11 knock-out with wildtype DOCK2. The progress of characterizing the function of KLF11 in lymphocyte recruitment and egress will be reported.
Citation Format: Hsin Chen, Timothy Schmidt, Ying Xu, Erick Lu, Jason G. Cyster. Oscillatory genes in lymphocyte retention and egress [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 A065.
Abstract A074: A Zap70-dependent negative feedback loop governs Lck activation by CD45
Authors: Courtney Adam H. , Kadlecek Theresa A. , Au-Yeung Byron , Weiss Arthur 
Published: November 2016

Abstract
The kinase Lck phosphorylates the T cell antigen receptor (TCR) complex when antigen is encountered and therefore its activity sets a critical threshold for T cell activation. Yet how Lck activity is regulated in resting or stimulated cells remains poorly understood. We have identified that a cryptic phosphosite within Lck, Y192, profoundly affects Lck activity when mutated. Notably, mutation of Y192 blocks critical TCR proximal signaling events including phosphorylation of the effector kinase Zap70 and subsequent calcium response. Accordingly, thymocyte development in retrogenic mice harboring a Y192 mutation is severely impaired. These mice are unable to produce mature T cells and accumulate double negative and double positive (CD4/CD8) thymocytes. We determined that these defects are caused by hyperphosphorylation of the canonical inhibitory phosphorylation site (Y505) within Lck's C-terminus. Lck's C-terminus is phosphorylated by the inhibitory kinase Csk and we have employed a regulatable reconstituted system to acutely inhibit Csk activity. Upon Csk inhibition, the phosphatase CD45 dephosphorylates Lck's C-terminus (Y505). Interestingly, mutation of Y192 disrupts CD45's ability to dephosphorylate Y505 and activate Lck. Because Y192 phosphorylation decreases in response to small molecule inhibition of Zap70, an Lck substrate, our findings support a mechanism of negative feedback. We predict that tonic or basal signaling events that occur in the absence of TCR ligand use negative feedback, including Y192 phosphorylation, to tune Lck activity. Because modulation of Lck activity impacts TCR sensitivity, feedback mechanisms are likely critical to establishing a threshold for T cell activation.
Citation Format: Adam H. Courtney, Theresa A. Kadlecek, Byron Au-Yeung, Arthur Weiss. A Zap70-dependent negative feedback loop governs Lck activation by CD45 [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 A074.
Abstract A076: Cutaneous microbiota drive the accumulation of IL-17A-producing T cells within the lungs
Authors: Constantinides Michael G. , Ridaura Vanessa K. , Belkaid Yasmine 
Published: November 2016

Abstract
Infectious agents are estimated to cause approximately 18% of cancers worldwide, supporting a link between microbial products and carcinogenesis. The microbiome consists of a diverse array of commensal microorganisms that reside at barrier sites of the human body and promote local immune homeostasis, but also provide the primary source of constitutive microbial stimulation. While recent work has demonstrated that intestinal commensals can influence immunity throughout the body, the distal effects of other microbial communities have not been fully explored. Here we show that application of distinct human commensals to the skin of mice induces the accumulation of IL-17A-producing T cells in the lungs. The induction of these cells occurs in a manner that is partially dependent on both antigen presentation and IL-23 signaling. Response kinetics and adoptive transfer experiments suggest that the T cells migrate from the skin-draining lymph nodes, while transcriptional analysis has identified specific chemokine receptors that facilitate trafficking to the lungs. Furthermore, in the context of a pulmonary challenge, cutaneous application of commensals promotes the production of IL-17A and recruitment of neutrophils to the lungs. This work demonstrates that the skin microbiome can enhance pulmonary immunity, but also has the potential to cause pro-oncogenic inflammation. Since IL-17A promotes tumor vascularization and neutrophils can contribute to the establishment of metastases, specific microbes at distal sites such as the skin may exacerbate the progression of lung cancer.
Citation Format: Michael G. Constantinides, Vanessa K. Ridaura, Yasmine Belkaid. Cutaneous microbiota drive the accumulation of IL-17A-producing T cells within the lungs [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 A076.
Abstract A090: Identify molecular mechanisms that regulate the GMP-AMP synthase (cGAS) activity
Authors: Li Tuo , Chen Zhijian J. 
Published: November 2016

Abstract
While checkpoint inhibitors are achieving stunning success in cancer treatment, one possible approach to improve the response rate is to enhance the initiation of anti-tumor immune response. Recently studies showed that the cytosolic DNA sensing pathway is essential for the innate immune response in dendritic cells to radiation treated tumor cells. Cytosolic DNA, as a danger signal, is sensed by the cyclic GMP-AMP synthase (cGAS), which produces the second messenger, 2'3'-cyclic AMP-GMP (cGAMP) to activate STING-mediated Type I interferon response. Despite the critical role of cGAS in anti-tumor immunity, how its activity is regulated remains poorly understood. To explore cGAS-regulating mechanisms in cells, we used mass spectrometry to study cGAS and its interacting partners during the course of DNA sensing. The results indicate that cGAS is phosphorylated at multiple serine and threonine residues. Mutagenesis experiments showed that the phosphorylation at Serine305 can potently inhibit the cGAMP-synthesis activity. Structural analysis illustrated that this phosphorylation site locates at the entrance of the active site, therefore the negatively charged phosphate group may sterically block the access of substrates, ATP and GTP. This serine is highly conserved in mammalian species, and locates within a cyclin kinase motif. Indeed, purified human CDK1-cyclin B complex, the dominant mitosis driver, can specifically phosphorylate this serine in vitro. The results suggest that the cGAS activity may coordinate with the cell cycle, and implies that the phosphorylation may limit the immunogenicity of tumor radiation therapy.
Note: This abstract was not presented at the conference.
Citation Format: Tuo Li, Zhijian J. Chen. Identify molecular mechanisms that regulate the GMP-AMP synthase (cGAS) activity [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 A090.
Abstract A095: Immunosuppressive plasmocytes regulate the development of NASH-induced HCC
Authors: Shalapour Shabnam , Karin Michael 
Published: November 2016

Abstract
Hepatocellular carcinoma (HCC), a rather common and lethal malignancy, is the prevalent common form of liver cancer, associated with chronic tissue damage caused by fat accumulation, environmental toxicants, viral infections, inflammation and stress. Although at present, hepatitis virus infections are the primary HCC risk factors, they will soon be replaced by hypernutrition and ethanol consumption, both of which cause hepatic steatosis. According to a recent CDC report the incidence of HCC continues to grow at an alarming yearly rate, in part due to the obesity epidemic. This has sparked a considerable effort to understand how non-alcoholic fatty liver disease (NAFLD) and its more aggressive manifestation, non-alcoholic steatohepatitis (NASH), drive HCC development. Although, many studies have confirmed that NASH to HCC progression is inflammation dependent, the role of adaptive immune responses in NASH-promoted HCC is largely unknown. We recently identified a type of B cells in both mouse and human prostate cancer (PC), that have potent immunosuppressive properties. Ablation of these immunosuppressive plasmocytes (ISP), enables nearly complete elimination of large and advanced PC tumors upon treatment with the immunogenic chemotherapeutic oxaliplatin. ISP are IgA-producing plasmocytes that express the immunosuppressive molecules IL-10 and PD-L1. In PCa, generation of ISP is driven by TGFβ, which is produced in large amounts by αSMA+ CAF, which also produce the B cell chemoattractant CXCL13. We therefore examined whether ISP are present in other tumors that are rich in TGFβ (and CXCL13)-producing αSMA+ myofibroblasts and confirmed their presence in two mouse models of liver cancers that develop in the context of chronic inflammation and fibrosis. Meanwhile, a strong correlation between circulating IgA and the degree of liver fibrosis was observed in patients suffering from NASH. Interestingly, accumulation of IgA and IL-10 expressing plasmocytes precedes HCC development and is not seen in mice that develop simple steatosis. The depletion of IL-10 and PD-L1-expressing ISP in livers of NASH-afflicted mice resulted in at least a 50% decrease in tumor burden accompanied by CTL activation and infiltration. Thus, a combination of anti-PD-L1 or other ISP-depleting treatment with a suitable immunogenic chemotherapeutic agent may result in more extensive HCC regression.
Citation Format: Shabnam Shalapour, Michael Karin. Immunosuppressive plasmocytes regulate the development of NASH-induced HCC [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 A095.
Abstract A096: Myeloid cells are required for pancreatic carcinogenesis and PD-1/PD-L1 checkpoint activation
Authors: Zhang Yaqing , Velez-Delgado Ashley , Mathew Esha , Li Dongjun , Mendez Flor M. , Flannagan Kevin , Rhim Andrew D. , Simeone Diane M. , Beatty Gregory L. , Magliano Marina Pasca di 
Published: November 2016

Abstract
Myeloid cells, including both macrophages and immature myeloid cells/myeloid derived suppressor cells (MDSCs), accumulate during the progression of pancreatic cancer. The goal of this study was to determine the effect of myeloid cell depletion on the onset and progression of pancreatic cancer, and to understand the relationship between myeloid cells and T cell-mediated immunity within the pancreatic cancer microenvironment.
Primary mouse pancreatic cancer cells were transplanted into CD11b-DTR mice. Alternatively, the iKras* mouse model of pancreatic cancer was crossed into CD11b-DTR mice. CD11b+ cells were depleted by Diphtheria Toxin treatment during tumor initiation or in established tumors. Depletion of myeloid cells prevented KrasG12D driven pancreatic cancer initiation.
Myeloid cells are required for sustained MAPK signaling in pancreatic epithelial cells during the onset of carcinogenesis, notwithstanding the expression of oncogenic Kras. In pre-established tumors, myeloid cell depletion arrested tumor growth and in some cases, induced tumor regressions that were dependent on CD8+ T cells. We found that myeloid cells inhibited CD8+ T cell anti-tumor activity by inducing the expression of Programmed cell death-ligand 1 (PD-L1) in tumor cells in an EGFR/MAPK dependent manner. Treatment with MEK inhibitors lowers the intratumoral expression of PD-L1 and renders the tumor susceptible to PD-1 blockade.
Our results show that myeloid cells support immune evasion in pancreatic cancer through EGFR/MAPK dependent regulation of PD-L1 expression on tumor cells. Derailing this cross-talk between myeloid cells and tumor cells is sufficient to restore anti-tumor immunity mediated by CD8+ T cells, a finding with implications for the design of immune therapies for pancreatic cancer.
Note: This abstract was not presented at the conference.
Citation Format: Yaqing Zhang, Ashley Velez-Delgado, Esha Mathew, Dongjun Li, Flor M. Mendez, Kevin Flannagan, Andrew D. Rhim, Diane M. Simeone, Gregory L. Beatty, Marina Pasca di Magliano. Myeloid cells are required for pancreatic carcinogenesis and PD-1/PD-L1 checkpoint 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 A096.
Abstract A105: Characterization of adenosine producing B cells in patients with head and neck cancer as well as of the influence of adenosine on B cell function
Authors: Jäkle Sandra S. , Brunner Cornelia , Hoffmann Thomas K. , Schuler Patrick J. 
Published: November 2016

Abstract
Introduction: Recently, we have shown that human regulatory B cells (Breg) and regulatory T cells (Treg) are the main producers of exogenous immune-suppressive adenosine (ADO) with the ectonucleotidases, CD39 and CD73, being the functional enzymes. Immune suppression in the tumor environment may cause increased tumor growth and metastasis. But the role of intracellular components of Breg and in response to ADO are not completely understood.
Methods: Peripheral blood mononuclear cells (PBMC) and tumor infiltrating lymphocytes (TIL) were isolated from patients with head and neck cancer (n = 20). Phenotypes, intracellular expression of phosphor-proteins of the B cell-receptor (BCR)-mediated signaling pathway and ADO production were determined by multicolor flow cytometry and luminescence. The influence of exogenous ADO on intracellular signaling pathways was determined by flow cytometry, western blot and PCR on healthy volunteers.
Results: In comparison to healthy donors, the frequency of Treg is increased while the frequency of Breg remains stable in the peripheral blood of cancer patients. For the Treg this effect is pronounced in the tumor microenvironment, while the B cells showed new phenotypic characteristics. The phosphorylation of the proteins of the intracellular BCR-pathway in healthy B cells are inhibited by treatment with ADO. In contrast, after BCR-specific stimulation, the secretion of inflammatory cytokines by B cells is increased in the presence of ADO.
Conclusion: Adenosine producing immune cells contribute to immune suppression in the tumor microenvironment and may promote tumor growth. Intracellular key regulators of ADO-production in Breg may serve as a therapeutic target in cancer patients.
Citation Format: Sandra S. Jäkle, Cornelia Brunner, Thomas K. Hoffmann, Patrick J. Schuler. Characterization of adenosine producing B cells in patients with head and neck cancer as well as of the influence of adenosine on B cell function [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 A105.