bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5690: Characterization of tumor growth and immune microenvironment in humanized NOG-EXL mice implanted with A549, MDA-MB-436 and A375 cells
Authors: Ghosh Srimoyee , Fiore Anne , Eberle Christoph , Wang Sarah , Mikule Keith , McEachern Kristen , Kumar Sujatha , Jenkins David , Sharma Geeta 
Published: August 2018

Abstract
Syngeneic mouse models are the most extensively explored mouse models for evaluation of immune-oncology therapeutic modalities in preclinical settings. One of the major limitations with syngeneic models is that both the tumor and the immune system is murine and thus do not express any human targets. Also, this precludes the evaluation of human clinical product (antibody or protein) mandating the synthesis and use of murine surrogates. Therefore, development of models of human tumors in mice with competent human immunity became an urgent need. Tumor-bearing, humanized NOG-EXL mice are a new and valuable preclinical testing platform for immuno-oncology, to simulate trials, evaluate multiple drugs alone or in combination, and produce predictive data both in cell line derived (CDX) and patient derived (PDX) models. With the objective of understanding the tumor growth and basal immune microenvironment in Hu-NOG-EXL mice (NOG mice humanized using CD34+ cells isolated from cord blood), we implanted three different human tumor cell lines (A549: Human Lung Carcinoma; MDA-MB-436: Triple Negative Breast Cancer; A375: Human Melanoma) in Hu-NOG EXL mice procured from Taconic, NY. The tumors were collected at a tumor volume of 1000-1500mm3, and profiled for the lymphoid and myeloid compartments using flow cytometry. The corresponding splenic compartment was also profiled to monitor the correlation or lack thereof between the tumor and splenic compartments. Finally the tumors were compared and categorized based on their basal infiltrates. The results demonstrated that Hu-NOG-EXL mice could be an useful tool to dissect the immune response in human tumors. It was possible to identify and quantitate the myeloid cells which are absent in a model that has been implanted with human PBMNC's (Peripheral Blood Mono Nuclear Cells) instead of human CD34 stem cells.
Citation Format: Srimoyee Ghosh, Anne Fiore, Christoph Eberle, Sarah Wang, Keith Mikule, Kristen McEachern, Sujatha Kumar, David Jenkins, Geeta Sharma. Characterization of tumor growth and immune microenvironment in humanized NOG-EXL mice implanted with A549, MDA-MB-436 and A375 cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5690.
Abstract 5696: Discovery of putative breast cancer antigens using genomics-driven immunoproteomics
Authors: Han David K. 
Published: August 2018

Abstract
Recent advances in cancer immunotherapeutics such as checkpoint inhibitors, chimeric antigen-receptor T cells, and tumor-infiltrating T cells (TIL) are now significantly impacting cancer patients in a positive manner. Although very promising, reports indicate no more than 25% of cases result in complete remission. One of the limitations of these treatments is the identity of cancer antigens in each patient as it is technically challenging to identify cancer antigens in a rapid fashion. Thus, identification of cancer antigens for each patient followed by targeted treatment will likely increase the efficacy of cancer immunotherapies. To achieve this goal, a combined technologies of deep genomic sequencing and personalized immune assessment platform was devised, termed Genomics-Driven Immunoproteomics (GDI). Using this technological platform, we report the discovery of 149 putative tumor antigens from human breast cancer patients. Significant numbers of these cancer antigens arise from single nucleotide variants (SNVs), as well as insertions and deletions that results into frame-shift mutations. We propose a general model of anticancer immunity and suggest that GDI platform may help identify patient-specific tumor antigens in a timely fashion for precision immunotherapies.
Citation Format: David K. Han. Discovery of putative breast cancer antigens using genomics-driven immunoproteomics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5696.
Abstract 5701: Verification of the methodology for evaluating tumor-infiltrating lymphocytes in colorectal cancer
Authors: Matsutani Shinji , Shibutani Masatsune , Maeda Kiyoshi , Nagahara Hisashi , Fukuoka Tatsunari , Tamura Tatsuro , Ohira Go , Yamazoe Sadaaki , Kimura Kenjiro , Toyokawa Takahiro , Amano Ryosuke , Tanaka Hiroaki , Muguruma Kazuya , Hirakawa Kosei , Ohira Masaichi 
Published: August 2018

Abstract
Background: The density of tumor-infiltrating lymphocytes (TILs) have been reported to reflect antitumor immune response and correlate with prognosis in malignancy. However, the methodology for evaluating the density of TILs by an immunohistochemical analysis differs among reports. The aim of this study was to verify the methodology for evaluating the density of TILs by immunohistochemical analysis and thereby identify the optimum methodology in clinical setting.
Methods: Three-hundred-thirteen patients who underwent curative operation for stage II/III colorectal cancer were enrolled. We retrospectively examined the density of TILs using immunohistochemical staining according to each method as follows: 1) subset of lymphocytes (i.e. CD4+/CD8+), 2) selected fields (i.e. at random or focusing on hot spots), 3) location in low-power field (i.e. the invasive margin [TILsIM] or the center of the tumor [TILsCT] or the surface of the tumor [TILsST]), and 4) location in high-power field (i.e. in tumor stroma [sTILs] or intra-tumor cells [iTILs] or total TILs [tTILs: sTILs+iTILs]). We then assessed the prognostic value of the density of TILsIM evaluated as described above. We also evaluated the correlation between the density of TILsIM and that of TILsCT/TILsST.
Results: In randomly selected fields, the densities of CD8+sTILsIM and CD8+tTILsIM were significantly associated with the survival. However, the densities of TILs evaluated via other methods were not associated with the survival. Furthermore, the density of CD8+TILsIM was significantly associated with that of CD8+TILsCT and CD8+TILsST.
Conclusions: We concluded that best and easiest way to evaluate the density of TILs in the clinical setting may be to assess the density of total CD8+TILs at the invasive margin in randomly selected fields.
Citation Format: Shinji Matsutani, Masatsune Shibutani, Kiyoshi Maeda, Hisashi Nagahara, Tatsunari Fukuoka, Tatsuro Tamura, Go Ohira, Sadaaki Yamazoe, Kenjiro Kimura, Takahiro Toyokawa, Ryosuke Amano, Hiroaki Tanaka, Kazuya Muguruma, Kosei Hirakawa, Masaichi Ohira. Verification of the methodology for evaluating tumor-infiltrating lymphocytes in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5701.
Abstract 5702: Characterization of circulating tumor cells during immune checkpoint inhibition in metastatic renal cell carcinoma and malignant melanoma
Authors: Zhang Tian , Park SinJung , Runyambo Daniella , Poellmann Michael J. , Reyes-Martinez Marco , Mahbooba Zahra , Green Rebecca , Lee Carrie , George Daniel J. , Armstrong Andrew J. , Hong Seungpyo , Wang Andrew Z. 
Published: August 2018

Abstract
Background: Although immune checkpoint inhibitors (ICIs) have shown efficacy in a range of solid tumors, there are no established circulating biomarkers able to identify early responders to treatment. Circulating tumor cells (CTCs) allow a non-invasive peripheral assessment of disease burden over time. We evaluated the prevalence of CTCs before and during treatment with ICIs.
Methods: Patients were enrolled prospectively at Duke Cancer Center and UNC Lineberger Cancer Center and selected for metastatic renal cell carcinoma (mRCC) and metastatic malignant melanoma (mMM) receiving standard of care immunotherapy. Using E-selectin for slowing cell rolling and a nanoparticle dendrimer based technology for cell capture with EpCAM, HER2, and EGFR, the CapioCyte platform was used for CTC capture at baseline, during treatment, and upon disease progression.
Results: We enrolled 5 subjects with mRCC and 4 subjects with mMM. Prior to treatment, subjects had a median of 293 CTCs/mL (all healthy volunteers (HVs, n=10) had &lt;8 CTCs/mL). All subjects had more CTCs at baseline than HVs. One subject had CTCs rise within the first 4 weeks on ICI treatment, which corresponded to clinical disease progression. Several other subjects showed a rapid decrease in CTCs within 4 weeks but increased at the time of disease progression. In most cases of disease control, CTCs decreased by at least 50% at the 4-week timepoint and increased at time of disease progression.
Conclusions: CapioCyte is a sensitive platform to detect CTCs in mRCC and mMM. Based on CTC detection, many patients had early response to ICI treatment, but rapid progression corresponding to clinical progression. This pilot data suggest that CTCs can be a valuable biomarker for monitoring the clinical benefit of cancer immunotherapies.
Citation Format: Tian Zhang, SinJung Park, Daniella Runyambo, Michael J. Poellmann, Marco Reyes-Martinez, Zahra Mahbooba, Rebecca Green, Carrie Lee, Daniel J. George, Andrew J. Armstrong, Seungpyo Hong, Andrew Z. Wang. Characterization of circulating tumor cells during immune checkpoint inhibition in metastatic renal cell carcinoma and malignant melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5702.
Abstract 5703: Immunoscore as prognostic biomarkers in patients with epithelial ovarian cancer
Authors: Lee Shin-Wha , Kim Min-Je , Kim Ju-hyun , Lee Young-Jae , Kim Yong-Man , Kim Yong-Man 
Published: August 2018

Abstract
Background: The analysis of single parameters alone may not provide sufficient insights about complex immune system-tumor interactions. This study is to validate the immune contexture as prognostic biomarkers in high-grade serous ovarian cancer (HGS-OC) and to find new era of immunoscore in HGS-OC.
Methods: We collected FFPE samples from 187 patients with HSOC and produced TMA samples. We accomplished the OPAL multiplex IHC assay for the quantitative analysis of immune markers, including CD4, CD8, CD20, FoxP3, PD-L1, and CK. Multiplex Biomarker Imaging and inForm® Image Analysis Software was used.
Results: FIGO stage III and IV patients were 84.5% (158/187). The optimal debulking surgery was done in 66.8% (125/187). The 3-year disease-free survival and 5-year overall survival were 35.1% and 50.0%, respectively. Any single marker was not related to the survival, including CD8, FoxP3, and PD-L1. However, high CD8:FoxP3 and CD8:PD-L1 ratios were correlated with good survival. In Cox regression model, the risk factors for HGS-OC survival were FIGO stage (HR 1.784, 95% CI: 1.295-2.457, p&lt;0.001) and platinum resistance (HR 4.257, 95% CI: 2.753-6.582, p&lt;0.001). Additionally, CD8:PD-L1 ratio was a favorable prognostic factor (HR 0.621, 95% CI: 0.042-0.917, p=0.017).
Conclusion: These findings indicate that although any single immune marker is not related to the survival, CD8:FoxP3 and CD8:PD-L1 ratios provide the positive correlation with the prognosis in HGS-OC; especially, CD8:PD-L1 ratio is prognostic biomarker that is comparable to clinical biomarkers. The next study for immunoscore is necessary to define immunoscore in ovarian cancer.
Citation Format: Shin-Wha Lee, Min-Je Kim, Ju-hyun Kim, Young-Jae Lee, Yong-Man Kim, Yong-Man Kim. Immunoscore as prognostic biomarkers in patients with epithelial ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5703.
Abstract 5714: SPADE identification of novel MDSC subsets
Authors: Cole Kathryn , Britton Holly , Warkentin Phyllis , Talmadge James E. 
Published: August 2018

Abstract
Myeloid derived suppressor cells (MDSC's) are a heterogeneous population of myeloid cells at varying stages of differentiation that occur in increased numbers in the blood of cancer patients. The phenotypes of MDSC's, are controversial but are generally subdivided into three phenotypes: macrophage (M-), granulocytic (G-) and immature (i-) MDSC's. Our studies used a single staining tube with antibodies to linage markers (CD3, CD19 and CD56), HLA-DR, CD11b, CD14, CD15, CD16, CD33, CD34, CD45, PD-L1 and lectin-like oxidized low-density lipoprotein receptor 1 (LOX-1). Mobilized apharesis products from lymphoma patients provided a product with a high frequency of MDSCs compared to normal donor blood samples. A total MDSC population (Lin-HLA-DR-CD11b+CD14+ and Lin-HLA-DR-CD11b+CD14-CD33+) was exported from FlowJo to Spanning tree progression analysis of density normalized events (Spade) in Matlab. This analysis identified nine MDSC sub-populations as nodes. Impressively, cells from the non-MDSC populations, including monocytes and granulocytes did not occur within these nodes. The SPADE analysis identified four M-MDSC nodes, four G-MDSC nodes and one iMDSC node. LOX-1 expression was limited to two G-MDSC and one M-MDSC subset. The nodes were differentiated based on CD14, CD15, CD33, CD16, LOX-1, and CD34 expression. The total populations were SPADE analyzed by overlaying non-MDSCs populations onto MDSCs and monocytes and granulocytes subset to nodes independent of MDSC nodes. The assessment of MDSC function used intracellular arginase-1 and nitric oxide synthetase-2 expression with the expected differential expression consistent with the M and G-MDSC subsets. The proportions of the different MDSC nodes varied between cancer patients and were generally at least a log higher than in the blood of normal donors. In summary, a SPADE analysis can cleanly identify MDSCs from monocytes and granulocytes and provide insight into novel MDSC subsets.
Citation Format: Kathryn Cole, Holly Britton, Phyllis Warkentin, James E. Talmadge. SPADE identification of novel MDSC subsets [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5714.
Abstract 5715: Monitoring immune cells-mediated cytolysis through impedance technology allows kinetic analysis of reagent efficacy
Authors: Cerignoli Fabio , Xi Biao , Guenther Garret , Muir Lincoln , Lamarche Brandon , Shields Jason , Abassi Yama 
Published: August 2018

Abstract
In vitro characterization of immunotherapy reagents efficacy and combination synergies is necessary before moving to expensive animal models and clinical studies. Current standard assays like Chromium-51 release, ATP-based luminescence cell monitoring or flow cytometry are difficult to implement in a high throughput environment and are based on end point methodologies that are unable to capture the full dynamic of the immune response. Here we validate an impedance-based platform for monitoring cytotoxic activity of immune cells in the context of cancer immunotherapy assays. The technology detects cell death and proliferation of adherent cells by measuring changes in conductance of microelectrodes embedded in 96 and 384-wells cell culture plates, without the use of labeling or cell modification. We present a large set of validation including CD19 Car T models, EpCAM/CD3 BiTE antibodies and checkpoint combination therapies with anti PD-1/PD-L1 and CTLA-4 antibodies. Data comparison with Annexin V staining/Flow Cytometry shows perfect correlation between the drop in impedance signal and % of apoptotic cells. Long time monitoring (&gt; 7 days) in combination with low effector:target ratios reveal the occurrence of resistance mechanisms in target cells and exhaustion in effector cells. Such dynamic response has been observed in animal models and patient clinical trials, but it is difficult to monitor in short time assays. Overall, our results demonstrate the value of such label-free approach in measuring the cytotoxic response across the temporal scale, an aspect that is otherwise very difficult to assess with more canonical end point assays but that is highly relevant when testing combinations. Thanks to the availability of 384-wells format and minimal sample handling, the technology is ideally suited for applications in large reagent validation screening or therapeutic protocol validation directly on patient samples.
Citation Format: Fabio Cerignoli, Biao Xi, Garret Guenther, Lincoln Muir, Brandon Lamarche, Jason Shields, Yama Abassi. Monitoring immune cells-mediated cytolysis through impedance technology allows kinetic analysis of reagent efficacy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5715.
Abstract 5739: Targeting EZH2 histone methyltransferase activity alleviates inflammatory bowel disease
Authors: Long Haixia , Zhou Jie , Wang Zhongyu , Huang Shuo , Zhu Bo 
Published: August 2018

Abstract
Objective: Inflammation plays crucial roles in the pathogenesis of inflammatory bowel disease (IBD). Enhancer of zeste homolog 2 (EZH2)-mediated trimethylation of histone 3 lysine 27 (H3K27m3) is critical to immune regulation. However, evidence is lacking to address the effect of EZH2 enzyme's activity on intestinal immune responses during IBD. This study aimed to explore the effects of targeting EZH2 methyltransferase activity on IBD progression in mice.
Design: EZH2's enzymatic activity inhibitor GSK343 or GSK126 were delivered by intravenous injection to C57BL/6 mice at the onset, or during the ongoing of IBD, induced by dextran sodium sulfate (DSS). Azoxymethane (AOM)/DSS protocol was applied to trigger colitis-associated colorectal cancer (CAC). Immune cells in the colon of colitis mice were analyzed by flow cytometry, immunofluorescence staining and myeloid-derived suppressor cells (MDSCs) deletion experiments. We differentiated mouse hematopoietic progenitor cells (HPCs) into MDSCs in vitro to investigate the effect of GSK343 on MDSCs generation.
Results: Inhibition of EZH2 activity significantly attenuated IBD-related symptoms and inflammation, substantially delaying the onset of CAC. Injection of GSK343 increased the number of functional MDSCs in the colons during IBD. Deletion of MDSCs abrogated the protective effects of GSK343 on IBD. Moreover, inhibition of EZH2 activity promoted the generation of MDSCs from HPCs.
Conclusion: Inhibition of EZH2 activity alleviates DSS-induced colitis by promoting MDSC development, and might serve as a new therapeutic strategy to treat IBD. Additionally, EZH2 inhibition enhances MDSC generation, therefore, EZH2 enzymatic inhibitors now in clinical trials for cancer treatment may hinder beneficial anticancer immunity responses.
Citation Format: Haixia Long, Jie Zhou, Zhongyu Wang, Shuo Huang, Bo Zhu. Targeting EZH2 histone methyltransferase activity alleviates inflammatory bowel disease [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5739.
Abstract 5740: PD-L1 overexpression induced by oncogenic KRAS and BRAF mutations through MAPK pathway activation in non-small cell lung cancer
Authors: Miura Yosuke , Sunaga Noriaki , Bao Pinjie , Girard Luc , Tsukagoshi Yusuke , Masuda Tomomi , Kasahara Norimitsu , Sakurai Reiko , Kaira Kyoichi , Hisada Takeshi , Minna John , Yamada Masanobu 
Published: August 2018

Abstract
Mutant KRAS and BRAF are important oncogenic drivers in non-small cell lung cancer (NSCLC), however, effective treatment strategies for most of these mutants have not been established. Immuno-oncology clinical trials have shown promising results of anti-programmed death 1 (PD-1) antibodies for a subset of NSCLC patients and tumor expression of programmed-death ligand 1 (PD-L1) is regarded as a predictive marker for anti-PD-1 therapy. We found that CD274 mRNA and PD-L1 protein expression were reduced in NSCLC lines by small interfering RNAs (siRNAs) targeting mutant KRAS, but not wild-type KRAS, and also by pharmacologic inhibitors of MEK and ERK. In addition, there was a positive correlation between CD274 expression and KRAS expression in NSCLC lines, and analyses of The Cancer Genome Atlas (TCGA) database revealed that NSCLCs with high KRAS expression exhibited higher levels of CD274 compared to the tumors with low KRAS expression among KRAS-mutant NSCLCs. Similarly, siRNA-mediated BRAF knockdown and inhibitors of BRAF and MEK reduced PD-L1 expression in BRAF-mutant NSCLC cells, suggesting that PD-L1 expression was also upregulated by oncogenic BRAF. Mechanistically, these results suggest that oncogenic KRAS and BRAF induce PD-L1 overexpression in NSCLCs by activation of the MEK-ERK pathway. For clinical translation, our results suggest that: 1. in NSCLCs the combination of KRAS and PD-L1 overexpression could be a surrogate predictive marker for anti-PD-1 treatment; and 2. that since the goal of checkpoint inhibitor immuno-oncology therapy is to inhibit the PD-L1 axis, that a combination of anti-PD-1 and targeted therapy to inhibit the MEK-ERK pathway could be beneficial.
Citation Format: Yosuke Miura, Noriaki Sunaga, Pinjie Bao, Luc Girard, Yusuke Tsukagoshi, Tomomi Masuda, Norimitsu Kasahara, Reiko Sakurai, Kyoichi Kaira, Takeshi Hisada, John Minna, Masanobu Yamada. PD-L1 overexpression induced by oncogenic KRAS and BRAF mutations through MAPK pathway activation in non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5740.