bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A038: Oncolytic virotherapy combination with DC-based immunotherapy for the treatment of melanoma
Authors: Banki Zoltan , Koske Iris , Barnstorf Isabel , Tripp Christoph , Stoitzner Patrizia , Romani Nikolaus , Wollmann Guido , Kimpel Janine , Laer Dorothee Holm-von 
Published: November 2016

Abstract
VSV-GP, a novel chimeric Vesicular Stomatitis Virus (VSV) pseudotyped with the glycoprotein of the lymphocytic choriomeningitis virus represents a promising oncolytic virus (OV) that preferentially targets and kills cancer cells. Release of tumor antigens and activation of immune response by OV therapy might support dendritic cell (DC)-mediated anti-tumor immunity. Thus in our study we analyzed the efficacy and immune mechanisms of the combination of VSV-GP oncolytic virotherapy with DC-based immunotherapy. Combination of VSV-GP therapy and DC-based vaccination was investigated in the syngeneic subcutaneous B16-OVA melanoma model. SIINFEKL-loaded CpG-activated DCs (DCVacc) and VSV-GP were applied intra- and peritumorally and immune responses were analyzed in the spleen and tumor tissues. The DCVacc/VSV-GP combination therapy resulted in a significantly improved survival compared to single treatments. Surviving mice from the DCVacc/VSV-GP treated group showed a long lasting anti-tumor immunity against B16-OVA and partial anti-tumor immunity against non-OVA B16 melanoma in rechallenge experiments. Analyzing specific cytotoxic T lymphocyte (CTL) responses induced by DCVacc and VSV-GP single and combination treatments we found that both DCVacc and DCVacc/VSV-GP induced comparable levels of OVA-specific CD8+ T cell responses. In addition a strong VSV N peptide-specific CD8+ T cell response was found upon VSV-GP and DCVacc/VSV-GP treatments. The improved therapeutic effect by the DCVacc/VSV-GP combination treatment correlated with increased numbers of tumor infiltrating lymphocytes (TIL) and elevated Tconv/Treg and CD8+/Treg ratios. Furthermore, depletion of CD8+ T cells but not NK cells abrogated the therapeutic effect of DCVacc/VSV-GP. Taken together, the combination of VSV-GP and DC-based immunotherapy might represent a promising therapeutic option for the treatment of melanoma.
Citation Format: Zoltan Banki, Iris Koske, Isabel Barnstorf, Christoph Tripp, Patrizia Stoitzner, Nikolaus Romani, Guido Wollmann, Janine Kimpel, Dorothee Holm-von Laer. Oncolytic virotherapy combination with DC-based immunotherapy for the treatment of melanoma [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 A038.
Abstract A046: Identification and validation of HCC-specific gene transcriptional signature for tumor antigen discovery
Authors: Petrizzo Annacarmen , Caruso Francesca P. , Tagliamonte Maria , Tornesello Maria Lina , Ceccarelli Michele , Costa Valerio , Aprile Marianna , Esposito Roberta , Ciliberto Gennaro , Buonaguro Franco M. , Buonaguro Luigi 
Published: November 2016

Abstract
A novel two-step bioinformatics strategy was applied for identification of signatures with therapeutic implications in hepatitis-associated HCC. Transcriptional profiles from HBV- and HCV-associated HCC samples were compared with normal liver tissue controls. Resulting HCC modulated genes were subsequently compared with different normal tissue samples. Two related signatures were identified, namely “HCC-associated” and “HCC-specific.” Expression data were validated by RNA-Seq analysis carried out on unrelated HCC samples and protein expression was confirmed according to the publicly available database at http://www.proteinatlas.org/. Among all, only two proteins (namely AKR1B10 and IGF2BP3) were found strictly HCC-specific with no expression in 18/20 normal tissues. Target peptides for vaccine design were predicted for both proteins associated with the most prevalent HLA-class I and II alleles. The described novel strategy showed to be feasible for identification of HCC-specific proteins as highly potential target for HCC immunotherapy (Petrizzo et al., Scientific Reports, in press).
Citation Format: Annacarmen Petrizzo, Francesca P. Caruso, Maria Tagliamonte, Maria Lina Tornesello, Michele Ceccarelli, Valerio Costa, Marianna Aprile, Roberta Esposito, Gennaro Ciliberto, Franco M. Buonaguro, Luigi Buonaguro. Identification and validation of HCC-specific gene transcriptional signature for tumor antigen discovery [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 A046.
Abstract A053: Targeting ICOS improves immune-mediated control of tumor growth in humanized mice
Authors: Burlion Aude , Corneau Aurélien , Marodon Gilles 
Published: November 2016

Abstract
Checkpoint blockade inhibitors are the most promising and effective strategy for T-cell mediated cancer immunotherapy of the past 20 years. Part of the anti-tumoral effect of these checkpoint inhibitors might be due to preferential targeting of regulatory T cells (Treg), essential for immune homeostasis. Here, we investigated whether the reported higher expression of ICOS on Treg than on regular T cells might be used as a flag to target human Treg to improve tumor-directed immune response. We report that a novel murine anti-human ICOS IgG1 mAb preferentially depleted Treg in NSG mice reconstituted with a human immune system from cord blood CD34+ cells, leading to an increased CD8 to Treg ratio. However, this was insufficient to affect growth of the breast cancer cell line MDA-MB-231 in humanized mice. We thus administered low dose cyclophosphamide that only moderately affected tumor growth to induce immunogenic cell death and improve tumor infiltration by human cells. Treatment of humanized mice with a combination of cyclophosphamide and the anti-ICOS mAb led to a marked reduction in tumor growth. Using mass cytometry (Cytof), we then analyzed the expression of 29 markers to quantify the main human and murine cell subsets in the tumor. We observed higher activation of CD8+ T cells in the combined-treatment group as judged by their higher expression of CD45RO and HLA-DR, relative to chemotherapy alone. Accordingly, depletion of CD8+ T cells with a mAb partly abolished the therapeutic effect of the combination, showing that these cells participated in tumor rejection. Notably, we also observed improved infiltration of human monocytes, human plasmacytoid dendritic cells and murine CD11b+CD11c+ cells in the tumor, suggesting that part of the effect of the combination therapy on tumor growth might proceed through these subsets. Altogether, our results demonstrate that ICOS, through its effect on regulatory T cells, release a brake in the immune response to tumors in humanized mice, and as such might be considered as a novel immune checkpoint inhibitor.&gt;
Note: This abstract was not presented at the conference.
Citation Format: Aude Burlion, Aurélien Corneau, Gilles Marodon. Targeting ICOS improves immune-mediated control of tumor growth in humanized mice [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 A053.
Abstract A059: Combinatorial proteomic analysis of the receptor programmed cell death (PD)-1 uncovers new checkpoint modulators
Authors: Peled Michael , Mor Adam 
Published: November 2016

Abstract
Programmed cell death (PD)-1 is one of the most important inhibitory checkpoints in T cells. Antibodies targeting PD-1 have elicited durable clinical responses in multiple tumor types and long-term remissions in some. Nevertheless, response to anti-PD-1 approaches is limited to a small fraction of patients and thus, a more complete understanding of this pathway should provide i) novel biomarkers for potential responders and ii) potential new therapeutic targets for refractory patients. We took an unbiased approach, exploiting high-resolution mass spectrometry, to uncover novel proteins that either interact with the cytoplasmic tail of PD-1 or are dephosphorylated downstream of the PD-1. We identified almost 20 proteins that interacted directly with the tail of PD-1, and approximately 100 proteins that their phosphorylation status was changed upon PD-1 signaling. Two of the more abundant proteins, EFHD2 and SH2D1A, were functionally analyzed for their contribution in mediating PD-1 inhibitory responses. Silencing EFHD2 resulted in abrogation of PD-1 inhibitory effect, including elimination of the ability of PD-1 signaling to inhibit cytokine secretion, cell proliferation, and cellular adhesion. Mechanistically, EFHD2 co-localized with PD-1 in the immunologic synapse, and was necessary for PD-1 clustering. In contrast, silencing SH2D1A augmented PD-1 function while over-expression of the same protein blocked PD-1 effects. We than discovered that SH2D1A physically competed with the phosphatase SHP2 for the same binding site on the tail of PD-1. Studying PD-1 interactome and phosphoproteome has thus identified new proteins that can modulate PD-1 function in opposite ways. These proteins should be further explored as potential targets in cancer.
Citation Format: Michael Peled, Adam Mor. Combinatorial proteomic analysis of the receptor programmed cell death (PD)-1 uncovers new checkpoint modulators [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 A059.
Abstract A069: Quantification of lymph node transit times reveals differences in the trafficking behavior of regulatory versus conventional CD4+ T cells
Authors: Tong Alexander 
Published: November 2016

Abstract
Regulatory T cells (Tregs) express the canonical marker Foxp3 and are critical for suppressing the immune response in homeostatic and inflammatory conditions. Despite how widely studied CD4+Foxp3+ Tregs are in mice, their physiologic trafficking and scanning behavior of antigen-presenting cells in secondary lymphoid organs (SLOs) have yet to be quantitatively analyzed in the intravital setting. Our laboratory has previously described the dynamics of T cell trafficking through SLOs and scanning of dendritic cells (DCs), revealing that CD4+ T cells and CD8+ T cells exhibit different transit kinetics through lymph nodes (LNs). On average, CD4+ T cells spend less time scanning for self-peptide/MHC (self-pMHC), dwell shorter in LNs, and egress faster compared to CD8+ T cells. Here we use flow cytometry and 2-photon laser scanning microscopy (2-PLSM) to quantitate the homeostatic trafficking behavior and surveillance strategy of Tregs in LNs and to compare their behavior to conventional T cells (Tconvs). Our data reveal surprising differences in Treg versus Tconv trafficking in mesenteric versus other peripheral LNs. We find that Treg LN transit time is heavily dependent on recognition of self-pMHC in peripheral but not mesenteric LN. Furthermore, we describe a novel imaging platform which enables high resolution intravital imaging of gut SLOs, especially mesenteric LN, for up to 10 hours. Finally, we use intravital 2-PLSM to quantify the contribution of self-pMHC recognition to Treg kinetics and scanning of DCs in peripheral and mesenteric LNs. These results add quantitative data to the emerging paradigm that self-pMHC interactions dynamically control homeostatic Treg retainment and localized suppressive function in peripheral LNs.
Citation Format: Alexander Tong. Quantification of lymph node transit times reveals differences in the trafficking behavior of regulatory versus conventional CD4+ T 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 A069.
Abstract A073: Epigenetic regulation of the Cd4 locus
Authors: Issuree Priya , Day Kenny , Littman Dan R. 
Published: November 2016

Abstract
CD4 helper and CD8 cytotoxic T cells originate from progenitor cells with binary potential. Transcriptional regulatory elements are key in establishing heritable epigenetic mechanisms to ensure gene-expression programs that maintain lineage identity. We show that, during thymocyte development, the co-receptor CD4 is regulated by a stage-specific regulatory element that ensures commitment to the CD4 lineage. Sustained CD4 expression in post-selection thymocytes requires this intronic element situated 3' to a silencer element previously shown to repress cd4 in CD8 cytotoxic T cells. Despite normal CD4 expression before selection, thymocytes lacking this intronic element failed to maintain CD4 expression following positive selection and were redirected to the CD8 lineage after MHC class II–restricted selection. We find that this regulatory element is key for propagating TET enzyme–mediated locus demethylation in CD4 T cells, a process that is likely initiated by another cis-element controlling CD4 expression at the double positive stage, before lineage commitment. This locus demethylation event is critical in ensuring heritable lineage identity and disruption of this process results in unstable CD4 expression and altered gene expression profiles. Cis and trans element interactions and molecular mechanisms governing heritable expression in response to distinct signals that dictate lineage ‘choice’ during T cell development will be presented.
Citation Format: Priya Issuree, Kenny Day, Dan R. Littman. Epigenetic regulation of the Cd4 locus [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 A073.
Abstract A078: Cutaneous microbiota in development of endogenous anti-melanocyte immunity
Authors: Vujkovic-Cvijin Ivan , Davis Jacquice , Singh Rasnik , Lee Kristina , Yu Zhiya , Restifo Nicholas , Wei Maria , Belkaid Yasmine 
Published: November 2016

Abstract
Despite major advances in immunotherapeutic approaches designed to bolster endogenous immune responses against tumors, metastatic melanoma remains associated with high mortality and rapid progression. Development of novel approaches toward enhancing endogenous immune responses against melanoma constitutes a critical step toward the management of disease. Of note, initiating immune responses against non-mutated melanocyte-specific protein antigens has shown efficacy in augmenting immunotherapies. Vitiligo is an autoimmune disease characterized by immune-mediated destruction of melanocytes, though the etiology of this disease remains poorly understood. Microbes have been recently found to have a profound effect on immune processes of the skin, including those that are associated with vitiligo progression. Identifying skin-resident microbes that initiate or exacerbate anti-melanocyte immunity, as well as the precise pathways that mediate these processes, may provide a novel framework for the development of immunotherapies to augment anti-tumor immune responses and efficacy of existing therapies. Thus, we have recruited a cohort of individuals with vitiligo and profiled their skin microbiomes at various body sites. We have isolated numerous vitiligo-associated bacteria and have adapted a mouse model of vitiligo in order to understand mechanisms of host-microbiome interaction in this setting. Interrogation of such a relationship between the microbiome and autoimmune destruction of melanocytes in vitiligo may lead to the identification of novel targets and pathways by which to augment melanoma immunotherapies.
Citation Format: Ivan Vujkovic-Cvijin, Jacquice Davis, Rasnik Singh, Kristina Lee, Zhiya Yu, Nicholas Restifo, Maria Wei, Yasmine Belkaid. Cutaneous microbiota in development of endogenous anti-melanocyte immunity [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 A078.
Abstract A100: Crosstalk between regulatory T cells and tumor-associated dendritic cells controls antitumor immunity in pancreatic cancer
Authors: Jang Jung-Eun , Hajdu Cristina H. , Miller George , Dustin Michael L. , Bar-Sagi Dafna 
Published: November 2016

Abstract
Pancreatic ductal adenocarcinoma (PDA) is marked by an abundant fibroinflammatory microenvironment. Regulatory T (Treg) cell infiltration constitutes a prominent feature of PDA. However, the immunomodulatory function of Treg cells in PDA remains poorly understood. Using orthotopic and autochthonous mouse models of PDA we have found that Treg cell ablation is sufficient to evoke effective anti-tumor immune response in early and advanced pancreatic neoplasia. This response is dependent on IFN-γ producing cytotoxic CD8+ T cells. We show that Treg cells engage in extended interactions with tumor-associated CD11c+ dendritic cells (DCs) and restrain their immunogenic function by suppressing the expression of costimulatory ligands necessary for CD8+ T cell activation. Consequently, tumor-associated CD8+ T cells fail to display effector activities when Treg cell ablation is combined with DC depletion. We propose that tumor-infiltrating Treg cells promote immune-tolerance by suppressing DC immunogenicity. Therapeutic manipulation this axis might provide an effective approach for the targeting of PDA.
Citation Format: Jung-Eun Jang, Cristina H. Hajdu, George Miller, Michael L. Dustin, Dafna Bar-Sagi. Crosstalk between regulatory T cells and tumor-associated dendritic cells controls antitumor immunity in pancreatic 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 A100.
Abstract A108: CD103+ intraepithelial T cells in high-grade serous ovarian cancer are phenotypically diverse TCRαβ+ CD8αβ+ T cells that can be targeted for cancer immunotherapy
Authors: Nijman Hans , Komdeur Fenne , Wouters Maartje , Workel Hagma , Brunekreeft Kim , Plat Annechien , Eggink Florine , Wisman Bea , Daemen Toos , Duiker Evelien , Hollema Harry , Bruyn Marco de 
Published: November 2016

Abstract
Introduction: CD103+ tumor-infiltrating lymphocytes (TIL) have been linked to specific epithelial infiltration and a prolonged survival in epithelial malignancies. However, whether these cells are induced as part of an ongoing anti-tumor immune response or represent non-specifically expanded resident or mucosal lymphocytes remains largely unknown.
Methods: CD103+ TIL were quantified in a cohort of ovarian and endometrial cancer patients by immunohistochemistry. Localization of CD103+ cells and co-expression of CD103 with CD3, CD8, CD16 and FoxP3 was assessed by immunofluorescence. Further phenotyping and functional experiments of CD103+ cells was performed mainly by flow cytometry on primary tumor digests.
Summary of the Data: In this study, we first confirmed that CD103+ TIL from ovarian and uterine cancer were predominantly localized in the cancer epithelium and were strongly correlated with an improved prognosis. We further demonstrate that CD103+ TIL were almost exclusively CD3+ TCRαβ+ CD8αβ+ CD4- T cells, but heterogeneously expressed T cell memory and differentiation markers. Activation of peripheral T cells in the presence of HGSC was sufficient to trigger induction of CD103 in over 90% of all CD8+ cells in a T cell receptor (TCR)- and TGFβR1-dependent manner. Finally, CD103+ TIL isolated from primary ovarian and uterine tumors showed signs of recent activation and dominantly co-expressed key immunotherapeutic targets PD-1 and CD27.
Conclusion: Our data indicate CD103+ TIL are formed as the result of an adaptive anti-tumor immune response that might be reactivated by (dual) checkpoint inhibition.
Citation Format: Hans Nijman, Fenne Komdeur, Maartje Wouters, Hagma Workel, Kim Brunekreeft, Annechien Plat, Florine Eggink, Bea Wisman, Toos Daemen, Evelien Duiker, Harry Hollema, Marco de Bruyn. CD103+ intraepithelial T cells in high-grade serous ovarian cancer are phenotypically diverse TCRαβ+ CD8αβ+ T cells that can be targeted for cancer 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 A108.
Abstract A117: CXCR1 is required for neutrophil recruitment to wounds and Kras-transformed cells in zebrafish
Authors: Powell Davalyn , Deng Qing , Huttenlocher Anna 
Published: November 2016

Abstract
Neutrophils are the first responder cells to sites of infection and tissue damage. Evidence from patient tumors and animal models of cancer also suggest that they are highly recruited to the tumor microenvironment, though their role there is still poorly understood. The larval zebrafish is an excellent model to study neutrophil migration and chemotaxis in vivo and is an emerging model for cancer development and progression. Here, we use the zebrafish to model Kras-driven oncogenesis in keratinocytes and glial cells. Beginning at 3 days post fertilization (dpf), we observe invasive EMT-like cell shape changes in oncogenic mutant Kras (KrasG12V) expressing cells as well as enhanced cell proliferation as marked by phospho-histone H3. Using fluorescently labeled transgenic lines, we demonstrate that neutrophils are recruited to transformed cells and that blocking this recruitment results in decreased proliferation of transformed cells, suggesting that neutrophils may play a tumor-promotional role in our model. To determine the method of neutrophil chemotaxis to transformed cells, we used Transcription Activator-like Effector Nuclease (TALEN) mutagenesis to generate zebrafish mutants for the chemokine receptor CXCR1, which is known regulate neutrophil chemotaxis. We demonstrate that CXCR1 is required for neutrophil chemotaxis to a tail-transection wound and to Kras-transformed cells in zebrafish. Together these data suggest that blocking CXCR1 activity may reduce neutrophilic inflammation in the tumor microenvironment which may in turn reduce tumor cell proliferation and slow tumor progression.
Citation Format: Davalyn Powell, Qing Deng, Anna Huttenlocher. CXCR1 is required for neutrophil recruitment to wounds and Kras-transformed cells in zebrafish [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 A117.