bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1462: Novel oncolytic virus armed with interleukin-21 enhances immune oncotherapy
Authors: Zhang Rong , Wang Tingting , Qing Yun , Sun Shuaijun , Liu Meili , Hu Fang , Fu Jin 
Published: August 2019

Abstract
Oncolytic viruses have elucidated the broad anti-tumor properties through selectively destroying tumor cells, promoting tumor antigen release and inducing the activation of immune response. Vaccinia virus (VV) has been engineered for tumor selectivity by the deletion of two essential genes (DDvv), viral growth factor (VGF) and thymidine kinase (TK). However, it still has certain obstacles, such as spread of virus, tumor microenvironment barrier, immune cell infiltration and tumor infiltration lymphocytes (TILs) proliferation. In the present study, we engineered the novel oncolytic mV01 and hV01 viruses, recombinant DDvv viruses carrying human interleukin-21 (hIL-21) or mouse IL-21 (mIL-21), respectively. mV01 and hV01 exhibited potent inhibition of various tumor cells with IC50 &lt; 0.5 MOI. When in combination with hNK cell, hV01 significantly enhanced the inhibition of cell proliferation in SK-HEP-1 cells and HepG2 cells as compared to mock virus. Animal studies showed that mV01 (i.t.) significantly reduced tumor burden in B16 C57/BL6 xenograph mice that were pre-treated with low dose cyclosporine A (i.p), compared to mock virus treatment. Simultaneously, mV01 regimens improved tumoral immune cell infiltration and TILs proliferation. Additionally, in HCT116 NCG xenograph mice, administration of hV01 (i.t.) exhibited significant inhibition of tumor growth (T/C &lt; 40%) when in combination with hNK cells (i.v). Together, these data revealed that V01 is a promising candidate for tumor immunotherapy through viral oncolysis and anti-tumor immunity.
Citation Format: Rong Zhang, Tingting Wang, Yun Qing, Shuaijun Sun, Meili Liu, Fang Hu, Jin Fu. Novel oncolytic virus armed with interleukin-21 enhances immune oncotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1462.
Abstract 1464: Inhibition of p38 MAPK in dendritic cells enhances their antigen presentation and induces Th17 T cell differentiation
Authors: Luo Yan , Barath Shreeder , Bahr Deborah A. , Dutta Navnita , Raja Geraldine , Cannon Martin J. , Knutson Keith L. 
Published: August 2019

Abstract
Dendritic cells (DCs) are the most potent antigen-presenting cells which bridges innate and adaptive immunity, but how DC-derived signals regulate and induce T cell lineage choices remains unclear. The p38 MAPK pathway plays an essential role in regulating cellular processes such as cell differentiation, growth, and death. In this study, SB203580 was employed to selectively inhibit p38 pathway in bone marrow derived DCs (BMDCs) to investigate the effects of this pathway on the characteristic phenotype and function of DCs, especially the induction on T helper cell differentiation. We found that inhibition of p38 increased the proliferation of BMDCs, but did not alter their phagocytic ability. Also, inhibition of p38 enhanced the activation of BMDCs, as evidenced by the up-regulated expression of DCs-related surface markers including CD80, CD86 and MHCII. However, the secretion levels of IL-12 and IL-10 in BMDCs were reduced significantly, whereas the level of IL-6 was not influenced by the p38 inhibitor. In addition, we immunized the mice with BMDCs vaccines and studied the production of antigen-specific Th17 T cell in spleen. Our data demonstrated that p38-inhibited DCs vaccine could induce more antigen-specific Th17 T cells than regular DCs vaccine in vivo. Collectively, these results support the hypothesis that the p38 pathway plays a critical role in the immunologic activation of DCs. Our findings suggest that inhibition p38 pathway in DCs may be a new strategy for generating potent DC vaccines for cancer immunotherapy.
Citation Format: Yan Luo, Shreeder Barath, Deborah A. Bahr, Navnita Dutta, Geraldine Raja, Martin J. Cannon, Keith L. Knutson. Inhibition of p38 MAPK in dendritic cells enhances their antigen presentation and induces Th17 T cell differentiation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1464.
Abstract 1490: Novel microbiome-derived peptides activate the host innate immune system by regulation of TLR signaling
Authors: Haria Dhwani , Kiefel Helena , Katlinskaya Yuliya , Jain Sunit , Weinmaier Thomas , Iwai Shoko , DeSantis Todd , Takeuchi Toshi , Dabbagh Karim , Graham Kareem 
Published: August 2019

Abstract
The gut microbiome is a key contributor to the maintenance of host physiology. At the same time, increasing evidence implicates microbiome dysbiosis as a key determinant of numerous metabolic and inflammatory disorders. It is, therefore, of paramount importance to understand the interactions between the host and gut microbiota. Second Genome has developed a proprietary, bioinformatics-driven discovery platform to identify novel microbiome-derived peptides with the potential to modulate host immune responses. We have leveraged this platform to evaluate immunomodulatory functions of novel, secreted peptides derived from gut-resident bacterial species Bifidobacterium longum and Bifidobacterium breve. Previously, the microbial genus Bifidobacterium (‘Bifido’) has been shown to be associated with enhanced dendritic cell functions and antitumor effects. Here, we identify Bifido-derived peptides that are putative agonists of certain murine and human Toll-like receptors (TLRs). These peptides induce secretion of pro-inflammatory cytokines such as TNF-α and IL-6 by in vitro-generated mouse dendritic cells and peritoneal macrophages in a TLR4 and CD14-dependent manner. One of the peptides, SG-A, also induces secretion of Th1-type cytokines and chemokines such as IL-21, GRO-α, and IP-10 by human monocytes and monocyte-derived dendritic cells. Moreover, in vivo administration of SG-A in mice elicited a systemic pro-inflammatory immune response in the absence of any secondary stimulus. Collectively, our results demonstrate the ability of a novel bacterial-derived peptide to engage the host innate immune system. Moreover, our findings validate the potential of the Second Genome discovery platform for identification of novel microbiome-derived agents that: i) have the ability to modulate host cell functions; and ii) may be developed into therapeutic agents for immune and inflammatory disorders.
Citation Format: Dhwani Haria, Helena Kiefel, Yuliya Katlinskaya, Sunit Jain, Thomas Weinmaier, Shoko Iwai, Todd DeSantis, Toshi Takeuchi, Karim Dabbagh, Kareem Graham. Novel microbiome-derived peptides activate the host innate immune system by regulation of TLR signaling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1490.
Abstract 1494: Galectin 9 associates with PDL1 expression and promotes gastric cancer cell invasion
Authors: Hill Charlotte , Cabrolier Camille , Cumsille Elisa , Arce Maximiliano , Pinto Mauricio P. , Bravo Maria Loreto , Muñoz Matias , Garrido Marcelo , Owen Gareth I. 
Published: August 2019

Abstract
Background: The development of immune checkpoint inhibitors (immunotherapy, such as anti-PD1) that induce a sustained T-cell immune response with anti-tumor activity has been a breakthrough in oncology practice. However, in gastric cancer (GC), sustained responses to anti PD-1 therapy are only observed in approximately 20% of patients. The expression of alternative immune checkpoints such as Galectin 9 (Gal-9) and Tim3 has been associated to anti-PD1 resistance in other cancer types. In search of the factors that render gastric tumors resistant to immunotherapy, we hypothesized that Gal-9 expression in gastric cancer cells may enhance metastasis and immunosuppression.
Methods: Bioinformatic analysis of gastric cancer data of patients with gastric adenocarcinoma from TCGA Database was performed. In vitro experiments with Gal-9 transfected gastric cancer cell line AGS were performed to elucidate Gal-9 gain of function effect on cell invasion and immune-suppressive proteins. Invasion assay using a matrigel coated transwell was performed within 24 hours of transfection. To determine changes in PDL1, E-Cadherin and N-Cadherin expression, cells were harvested 24h after transfection to analyze protein and mRNA levels through Western Blot and RT-PCR respectively.
Results: TCGA database analysis demonstrate that Gal-9 expression is significantly correlated to PDL-1 expression in gastric cancer; furthermore, it was also positively correlated to immune cell markers such as FOXP3. In accordance, in vitro analysis demonstrates that exogenous expression of GAL9 results in an increase in PDL-1 protein and greater invasive potential of the AGS cell line.
Conclusion: Taken together our results suggest that further studies should focus on the role played by Gal-9 is the establishment of an immune suppressive microenvironment in gastric tumors.
FONDECYT 1180241, 1180173. CONICYT FONDAP 15130011, IMII P09/016F
BMS CA209-8F3
Citation Format: Charlotte Hill, Camille Cabrolier, Elisa Cumsille, Maximiliano Arce, Mauricio P. Pinto, Maria Loreto Bravo, Matias Muñoz, Marcelo Garrido, Gareth I. Owen. Galectin 9 associates with PDL1 expression and promotes gastric cancer cell invasion [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1494.
Abstract 1495: Alternative humanized PD-1 mouse models provide more options for PD-1 antibody efficacy study in vivo
Authors: Lin Qing , Ma Huimin , Zhang Xiaoyu , Li Hengbin , Yang Wenjing , Yang Zhewei , Shen Xingchen , Ji Qunsheng 
Published: August 2019

Abstract
The Programmed Death-1 (PD-1) binding to its ligands PD-L1 and PD-L2 plays a critical role in suppression of T cell function and tumor immune evasion. Blocking antibodies against PD-1 have been shown to induce durable antitumor responses in multiple cancers in many clinical trials. So a well-characterized mouse model is essential for preclinical studies of antibodies that target human PD-1. Here we generated several humanized PD-1 knock-in mouse models, one expresses a hybrid PD1 protein by replacing the amino acids that involve in binding to PD-L1 (mostly IgV domain) with the human counterpart in both C57BL/6J and Balb/C genetic background, another one have both the IgV domain and signal peptide replaced by human counterpart. These mouse models were confirmed by PCR and southern blotting. And homozygous mouse models from these different strategies were also successfully generated and both of them could survive and the birth rate were very similar to heterozygous and wild type littermates. Staining for human and mouse PD-1 in stimulated CD8+ and CD4+ T cells indicate the up regulated expression of human PD-1 and absence of mouse PD-1 in these mouse model. Homozygous human PD-1 knock-in mice displayed normal development, and no obvious signs of autoimmunity for at least six months, whereas PD-1 knockout mice developed tissue-specific autoimmunity. With these human PD-1 knock-in mice engrafted with MC38 and treated with anti-human PD-1 antibodies, we confirmed the binding of anti-human antibody to chimeric PD-1 protein, and found anti-human PD-1 antibodies could significantly inhibit tumor growth in these models. Head to head comparison of these mice with current commercial available models for in vivo efficacy studies are undergoing and will reveal how the signal peptide effect the protein refolding or signaling transduction pathway for these ‘human-mouse’ chimeric proteins. In summary, these human PD-1 knock-in mouse models are functional and can be used to evaluate anti-human PD1 antibodies in vivo, we provide more options for antibodies which is targeting PD-1.
Citation Format: Qing Lin, Huimin Ma, Xiaoyu Zhang, Hengbin Li, Wenjing Yang, Zhewei Yang, Xingchen Shen, Qunsheng Ji. Alternative humanized PD-1 mouse models provide more options for PD-1 antibody efficacy study in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1495.
Abstract 15: Targeting vismodegib-resistant medulloblastoma using novel hedgehog pathway inhibitor and miR-29b mimic
Authors: Kumar Virender , Sethi Bharti , Kumar Vinod , Mcguire Timothy R. , Coulter Don W. , Mahato Ram I. 
Published: August 2019

Abstract
The purpose of this study to develop targeted liposomes of MDB5 and miR-29b combination for medulloblastoma (MB) treatment. Due to high heterogeneity and diverse genetic make-up, MB treatment is a challenge. Aberrant activation of hedgehog (Hh) pathway regulates cell growth, cancer stem cell (CSC) proliferation, and tumorigenicity in sonic Hh subgroup of MB. Further, Hh signaling regulates yes-associated protein 1 (YAP1) and glutaminolysis for energy need of tumor cells. GDC-0449 a smoothened receptors (SMO) antagonist treats (SHH)-MB initially, but resistance develops after repeated administration. Cholesterol potentiates Hh pathway independent of SHH by binding directly to the SMO. On the other hand, our RNA-seq and miRNA profiling confirmed downregulation of tumor suppressor miR-29b-3p in human MB samples. miR-29b control genes of apoptosis; p53, MDM2, AKT2, and cholesterol biosynthesis including HMGCR and SREBP1. We recently synthesized a potent GDC-0449 analog MDB5 (SMO inhibitors), which binds strongly to various Smo-mutants compared to GDC-0449. We found that a combination of MDB5 and miR-29b can treat MB synergistically. When we modified miR-29b backbone with 2-O’-methoxyethyl phosphorothioate (OMe-PS-miR-29b-3p), it showed enhanced stability in 50% serum. We designed a cationic lipid MDC2 for liposomal delivery of MDB5 and miR-29b1 simultaneously. Liposomes were prepared using film hydration technique and characterized for particle size and zeta potential, drug loading and release profile, miRNA complexation, stability, and transfection efficiency. These liposomes incorporated 88% MDB5 when the drug to phospholipid molar ratio was kept at 5%. Complete complexation was observed at N/P ratio of 3:1. These liposomes when loaded with green fluorescent protein (GFP) siRNA, resulted in 70% of signal silencing into DAOY MB cells (Shh driven). Liposomal MDB5 had higher cytotoxicity in DAOY cells compared to GDC-0449. Further, MDB5 and OMe-PS-miR-29b loaded liposomes resulted in higher, cytotoxicity and % of apoptosis, G0-G1 phase arrest, and decreased target gene expression in DAOY cells. Combination of drugs to simultaneously target multiple pathways related to Hh, glutaminolysis, cholesterol biosynthesis, and apoptosis has the potential to treat MB. Successful completion of this study will provide a nanomedicine for treating SHH-MB and other brain tumors.
Citation Format: Virender Kumar, Bharti Sethi, Vinod Kumar, Timothy R. Mcguire, Don W. Coulter, Ram I. Mahato. Targeting vismodegib-resistant medulloblastoma using novel hedgehog pathway inhibitor and miR-29b mimic [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 15.
Abstract 1505: Tumor associated antigen uptake tracking following immuno-radiotherapy
Authors: Christensen Esben , Ringgaard Lars , Brus Anja , Kjaer Andreas , Hansen Anders E. , Andresen Thomas L. 
Published: August 2019

Abstract
Immuno-radiotherapy is a promising strategy for generation of immunologic cancer recognition, rejection and induction of anti-cancer memory. Radiotherapy (RT) causes single or double strand DNA breaks in a dose dependent manner leading to immunogenic cell death of cancer cells and induction of type 1 interferons. Furthermore, RT increases MHCI expression on cancer cells and infiltration of cytotoxic T cells. Combined, these effects make RT a potent primer of anti-cancer immune responses. The most promising approaches in anti-cancer immunotherapy is to augment the adaptive immune response through danger associated molecular patterns signaling, including toll-like receptor (TLR) agonists. Optimally, these interventions should be given when tumor-associated antigen (TAA) uptake and presentation peaks. Previous studies on TAA uptake have mostly focused on in vitro or ex vivo assays to mimic the in vivo mechanisms. In the present study, we investigate the in vivokinetics of TAA uptake and trafficking using stably transfected mCherry-transfected B16F10 melanoma. B16F10 transfected with mCherry, a pH-stable fluorescent protein, allows tracking by e.g. flow cytometry in both cancer cells and phagocytosing populations. In vivo trafficking of mCherry fluorescence was investigated in mice treated with RT alone or in combination with TLR7 agonists given locally or systemically. Following treatment, TAA-uptake, -trafficking, and activation of relevant immune populations was evaluated in tumors or tumor draining lymph nodes (tdLNs). Increased TAA uptake was observed in MHCII high populations compared to MHCII low across all phagocytosing populations in tumors. The highest uptake (MFI of mCherry) was found in patrolling monocytes (CD11b+CD11c-Ly6c-CX3CR1high) and tumor-associated macrophages (CD11b+CD11c+CD64+). Interestingly, we exclusively found increased mCherry signal in resident cDC1s in tdLNs after treatment. RT led to a diminished population of migratory CD103+ cDC1s in tumors and we did not observe any increase in mCherry+ CD103+ cDC1s in tdLNs. We did not observe any mCherry signal in spleens - indicating that no cancer-specific immune response are mounted from the spleen. The results also indicate that TAA antigen is trafficked to tdLNs primarily by monocytes or by lymphatic drainage.
Citation Format: Esben Christensen, Lars Ringgaard, Anja Brus, Andreas Kjaer, Anders E. Hansen, Thomas L. Andresen. Tumor associated antigen uptake tracking following immuno-radiotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1505.
Abstract 1506: Lymph node metastasis in clinical breast cancer is significantly promoted by myeloid-derived lymphatic endothelial cell progenitors
Authors: Volk-Draper Lisa D. , Patel Radhika , Bhattarai Nihit , Yang Jie , Ran Sophia 
Published: August 2019

Abstract
Introduction: Lymph node (LN) metastasis, a key prognostic factor for poor survival of breast cancer (BC) patients, directly depends on tumor lymphangiogenesis. We previously showed in orthotopic BC models that lymphangiogenesis is strongly promoted by tumor-mobilized myeloid-derived lymphatic endothelial cell (LEC) progenitors (M-LECP) and that M-LECP density correlates with lymphatic metastasis. The goals of this study were to determine the blood levels of M-LECP, their tumor density and correlation with metastasis in clinical human BC.
Methods: Circulating CD14+ cells from BC patients (N=25) and healthy donors (N=24) were analyzed for expression of lymphatic-specific markers. Specimens from BC patients (N=104) along with normal mammary tissues (N=6) were co-stained with antibodies against myeloid and lymphatic markers including CD68, CD14, CD18 as well as LYVE1, podoplanin, and VEGFR-3. Sections were also double-stained to identify LYVE1+ cells expressing lymphoid, M2-type macrophage, and stem cell markers. Densities of tumor CD68+ macrophages, LYVE1+ vessels, and CD68+/LYVE1+ double-stained M-LECP were quantified and correlated with node status and other parameters. Pro-metastatic potential of experimentally produced mouse M-LECP was determined by injecting in vitro differentiated myeloid-lymphatic cells into mice bearing syngeneic EMT6 breast tumors.
Results: 92% of BC patients had monocytes expressing at least one lymphatic marker compared 2% of healthy donors. More than 70% of breast tumors contained M-LECP with density ranging from 2 to 50 cells per high-power field. Tumor-recruited M-LECP express specific markers of myeloid but not lymphoid lineages as well as M2-type, and stem cell markers. Tumors with high density (&gt;20 cells/field) of M-LECP were significantly more likely to belong to aggressive sub-groups (HER2+ and TNBC) and present with lymph node metastasis (P-value &lt;0.02).
Conclusion: These data show for the first time that human breast tumors recruit significant amount of immature myeloid cells with lymphatic phenotype and vessel-promoting properties. Such cells are largely absent from normal breast tissues. Statistical analyses show that M-LECP can significantly contribute to formation of new lymphatic vessels leading to increased nodal metastasis.
Citation Format: Lisa D. Volk-Draper, Radhika Patel, Nihit Bhattarai, Jie Yang, Sophia Ran. Lymph node metastasis in clinical breast cancer is significantly promoted by myeloid-derived lymphatic endothelial cell progenitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1506.