bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3128: Immune microenvironment of colorectal tumors and matched liver metastases
Authors: Dagenborg Vegar J. , Marshall Serena Elizabeth , Grzyb Krzysztof , Fretland Åsmund A. , Lund-Iversen Marius , Mælandsmo Gunhild M. , Børresen-Dale Anne-Lise , Ree Anne H. , Edwin Bjørn , Yaqub Sheraz , Flatmark Kjersti 
Published: August 2018

Abstract
Introduction: The presence of tumor-infiltrating lymphocytes, in particular T-cells in the tumor and its microenvironment, has been shown to be associated with prognosis in primary colorectal cancer (CRC) and CRC liver metastases (CLM). In this study we examined T-cell composition in the immune microenvironment in surgical specimens from 64 cases with CRC and resectable CLM.
Methods: Patients were enrolled in the Oslo-CoMet randomized trial (NCT 01516710). CRC and corresponding CLM were examined by immunohistochemistry to quantify all T-cells (Ttot) and subpopulations of cytotoxic (CTL), helper (TH), and regulatory T-cells (Treg). Densities of T-cells and subtypes (cells/mm2) were calculated at T-cell hotspots in the invasive margin (IM) and intra-tumoral (IT) locations. Median densities with interquartile ranges were calculated and compared for each region in CRC and CLM.
Results (Table 1): The highest density of Ttot was observed in the IM for both primary CRC and CLM, with the density in CLM being two-fold higher than CRC (CLMIM median 2853 cells/mm2 vs CRCIM 1257 cells/mm2; p&lt;0.001). For IT regions, the density of Ttot was much lower than in IM, and slightly higher in CRC compared to CLM (CRCIT median 486 vs CLMIT 332; p=0.02). Examining T-cell subtypes, the differences in CTL and TH mirrored Ttot, with the highest densities in the IM (CLMIM&gt;CRCIM) and lower densities in IT regions (CLMIT&lt;CRCIT). For the Treg, the IM densities were similar, while for IT, again, the density was lower in CLM than CRC.
Conclusion: In this study, we analyzed the immune microenvironment in matched CRC and CLM surgical specimens. We are currently analyzing associations with long-term outcome and results will be presented at the conference.
Table 1: Median T-cell density (interquartile range).CRCIMCLMIMCRCITCLMITTtot1257 (931 - 1735)2853 (2305 - 3813)486 (285 - 704)332 (189 - 564)CTL497 (315 - 722)1083 (762 - 1426)106 (51 - 209)99 (49 - 219)nsTH759 (584 - 983)1888 (1449 - 2745)348 (192 - 480)198 (118 - 383)Treg222 (155 - 375)233 (126 - 375)ns144 (75 - 225)43 (22 - 82)CRC and CLM densities at each location (IM and IT) were compared using the Mann-Whitney U test. P-values were &lt;0.05 for all comparisons unless indicated by ns.
Citation Format: Vegar J. Dagenborg, Serena Elizabeth Marshall, Krzysztof Grzyb, Åsmund A. Fretland, Marius Lund-Iversen, Gunhild M. Mælandsmo, Anne-Lise Børresen-Dale, Anne H. Ree, Bjørn Edwin, Sheraz Yaqub, Kjersti Flatmark. Immune microenvironment of colorectal tumors and matched liver metastases [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 3128.
Abstract 313: An Akt3 splice variant lacking the serine 472 phosphorylation site promotes apoptosis and suppresses mammary tumorigenesis
Authors: Hazan Rachel B. 
Published: August 2018

Abstract
The Akt pathway is a well-known promoter of tumor malignancy. Akt3 is expressed as two alternatively spliced variants, one of which lacks the key regulatory serine 472 phosphorylation site. Whereas the function of full-length Akt3 isoform (Akt3/+S472) is well-characterized, that of Akt3/-S472 isoform remains unknown. Despite being expressed at a substantially lower level than Akt3/+S472 in triple negative breast cancer cells, specific ablation of Akt3/-S472, enhanced, whereas overexpression, suppressed mammary tumor growth-consistent with a significant association with patient survival duration relative to Akt3/+S472. These effects were due to striking induction of apoptosis, which was mediated by Bim upregulation, leading to conformational activation of Bax and caspase-3 processing. Bim accumulation was caused by marked endocytosis of EGF receptors with concomitant ERK attenuation, which stabilizes BIM. These findings demonstrate an unexpected function of an endogenously expressed Akt isoform in promoting - as opposed to suppressing - apoptosis, underscoring that Akt isoforms may exert dissonant functions in malignancy.&lt;!–EndFragment–&gt;
Citation Format: Rachel B. Hazan. An Akt3 splice variant lacking the serine 472 phosphorylation site promotes apoptosis and suppresses mammary tumorigenesis [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 313.
Abstract 3130: Immune profiling in uterine papillary serous carcinoma cancer patients reveals distinct subpopulations and clinical outcomes
Authors: Vidal Angela Rynne , Lu Karen H. , Mok Samuel C. 
Published: August 2018

Abstract
Uterine papillary serous carcinoma (UPSC) is a rare but aggressive type of endometrial cancer (EC) that represents 10% of cases of EC but accounts for 40% of EC deaths. Patients with UPSC have poor survival rates, a high risk of recurrence and frequently metastasize to the lymph nodes and the omentum. The mechanisms that drive UPSC progression have not been elucidated yet and immune profiling can be a valuable tool to understand the different patient outcomes. In this work, we used formalin fixed paraffin embedded (FFPE) tumor samples from a cohort of 140 patients with UPSC, the largest used to date, to study a panel of 7 immune markers by multiplex immunofluorescence, using the OpalTM system (Perkin Elmer) in the same tissue section. Samples were imaged with Vectra 3.0 multispectral microscope (Perkin Elmer) and images were analyzed using Visiopharm software. Tumor samples from primary, metastatic and recurrent sites were used to study the tumor microenvironment. We observed significant differences in the tumor-infiltrating immune cells between patients that recurred and those that did not. Similarly, immune subpopulations distinguished patients with metastasis compared to those with a less aggressive form of UPSC. Spatial distribution of cytotoxic T cells (CD8+ GranzymeB+) and cancer cells was also found to significantly correlate with overall patient survival. Collectively, our work shows the immune populations play a role in patient outcomes and should be taken into account for future therapeutic strategies.
Citation Format: Angela Rynne Vidal, Karen H. Lu, Samuel C. Mok. Immune profiling in uterine papillary serous carcinoma cancer patients reveals distinct subpopulations and clinical outcomes [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 3130.
Abstract 3131: Acute myeloid leukemia derived SDF1 repels tumor infiltrating lymphocytes in the bone marrow microenvironment
Authors: Shafat Manar S. , Abdul-Aziz Amina A. , Marlien Christopher , Piddock Rachel , Bowles Kristian M. , Rushworth Stuart A. 
Published: August 2018

Abstract
Introduction: Acute myeloid leukaemia (AML) is an age-related disease with a median age at diagnosis of 71. Combined with co-morbidities, survival of patients with AML above this age bracket is poor with 90% of older adults dying of their disease. Even in younger patients who achieve remission with chemotherapy, relapse is common and occurs from minimal residual disease sequestered in protective niches in the bone marrow microenvironment (BMM). AML as a disease is highly dependent on the bone marrow microenvironment and accordingly it is envisaged that improved outcomes will come from novel treatment strategies derived from an improved understanding of the biology of AML within the bone marrow and their interaction with the immune cells therein.
Objective: Here, we investigate a possible immune evasive mechanism imparted by AML blasts attributed to their localization within the BMM.
Methods and Results: Using RNA-seq data generated from bone marrow derived AML (BM-AML) compared to peripheral blood derived AML (PB-AML) (GEO ID: GSE49642, GSE48846) we identified SDF-1 as the most differentially expressed in favour of BM-AML. Further investigation using matched primary clinical samples (BM verses PB) by real-time PCR analysis and ELISA confirmed the in-silico findings. In addition, primary AML engrafted into NSG mice demonstrated high SDF-1 in the BM derived AML blasts compared to AML blasts derived from the spleen. Lentiviral knock-down of SDF-1 in the AML blasts impaired blast engraftment and prolonged survival of the animals. SDF1-mediated migration of T-cell subsets have been previously identified using varying concentrations of SDF1. We therefore, investigated the migration of CD8+ T cells when co-cultured with AML. We show that CD8+ T-cells migrate away from AML when in culture and this fugetaxis is reduced by the knock-down of SDF1 in the blasts.
Conclusion: We conclude that SDF-1 is secreted by the AML blasts within the BMM contributing to fugetaxis of CD8+ cells away from the blasts. Implications of these finding suggest a possible immune evasive mechanism by the blasts that can be manipulated to potentiate CD8+ infiltration into the AML bone marrow.
Citation Format: Manar S. Shafat, Amina A. Abdul-Aziz, Christopher Marlien, Rachel Piddock, Kristian M. Bowles, Stuart A. Rushworth. Acute myeloid leukemia derived SDF1 repels tumor infiltrating lymphocytes in the bone marrow microenvironment [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 3131.
Abstract 3138: Key role of secreted kinase FAM20C on tumor associated macrophage (TAM) leading to pancreatic cancer progression
Authors: Im Jieun , Lee Yu-Sun , Choi Sun Il , Choi Beom-Kyu , Jeon A-Ra , Park Sang Hyun , Lee Min-Kyeong , Kim Joon-Ki , Kim Yun-Hee 
Published: August 2018

Abstract
FAM20C reported as a novel secreted kinase has the potential of phosphorylation on consensus motif, S-x-E/pS, of secretory proteins or ectodomain of membrane proteins. Numerous substrate candidates through prediction implied FAM20C has the function on tumor microenvironment, however, function and regulatory mechanism of cancer progression by FAM20C has not been defined yet. As tumor associated macrophage (TAM) changes to have the tumor supporting phenotype in response to various environmental stimuli, TAM is the potent regulatory target of FAM20C in tumor microenvironment. In this study, we hypothesized that the secreted kinase FAM20C in tumor microenvironment can support pancreatic cancer progression by regulating TAM contents or polarization. In pancreatic orthotopic xenograft model of FAM20C-overexpressing tumor cells, the tumor growth rate was enhanced and TAM contents (F4/80+/CD11b+/MHCII+) were significantly increased compared to control group, while total macrophage population between two groups had no difference. Moreover, the high level of TAM contents was sustained in the presence of FAM20C till the late stage of tumor progression. In addition, infiltrated tissue macrophages were polarized into TAM by FAM20C treatment Furthermore, increased TAM population by FAM20C suppresses the CD8+ cytotoxic T cell proliferation with anti-tumor function. Collectively, FAM20C might be a key regulatory factor in pancreatic cancer progression by promoting polarization of TAM.
Citation Format: Jieun Im, Yu-Sun Lee, Sun Il Choi, Beom-Kyu Choi, A-Ra Jeon, Sang Hyun Park, Min-Kyeong Lee, Joon-Ki Kim, Yun-Hee Kim. Key role of secreted kinase FAM20C on tumor associated macrophage (TAM) leading to pancreatic cancer progression [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 3138.
Abstract 3139: Innate immune cells expressing myeloperoxidase directly inhibit tumor NF-κB transcriptional activation during tumor initiation
Authors: Liu Tracy W. , Gammon Seth T. , Piwnica-Worms David 
Published: August 2018

Abstract
Neutrophils are considered the primary defenders of the innate immune system. However, in the context of cancer, the role of neutrophils is complex where they can be host protecting or pro-tumorigenic. For example, myeloperoxidase (MPO), the major protein in neutrophils, produces reactive oxygen species (ROS); ROS can lead to tumor regression from cell cytotoxicity or cause DNA-damage resulting in genetic mutations triggering tumor initiation/progression. Using the melanoma cell lines, B16F10, stably expressing a NF-κB-driven Firefly luciferase (FLuc) reporter or an IκBα-FLuc fusion reporter gene, co-culture studies in vitro with bone marrow-isolated-neutrophils from C57BL/6 animals demonstrated inhibition of NF-κB transcriptional activation in a MPO activity-dependent manner. Using bioluminescence imaging with luminol, neutrophils pre-stimulated with 50uM phorbol myristate acetate (PMA) demonstrated an increase in MPO activity by 20.3 ± 2.4 fold over unstimulated neutrophils. When B16F10 reporter cells were co-cultured with PMA pre-stimulated neutrophils, we observed inhibition of IκBα degradation by 33.0% ± 11.9%, resulting in a decrease in NF-κB transcriptional activation compared to co-culture studies with unstimulated neutrophils. The role of neutrophils during B16F10 tumor initiation and growth was compared in C57BL/6 and syngeneic MPO-null mice. Utilizing intravital imaging with skinfold window chamber animal models and imaging reporters, we evaluated in real-time, the recruitment of MPO-expressing cells and tumor NF-κB activation in vivo. Mean NF-κB transcriptional activation within the tumor compartment in MPO-null mice was 42.2% ± 1.6% greater compared to wild type animals. Tumor growth and survival curves demonstrated that B16F10 tumors grew slower in wild-type animals (mean survival of 26.8 days) compared to MPO-null animals (mean survival time of 23.4 days). Using an MPO inhibitor, 4-aminobenzoic acid hydrazide (4-ABAH), we pharmacologically mimicked the MPO-null phenotype in C57BL/6 animals (40mg/kg intraperitoneal injection twice daily). B16F10 tumors grew slower in C57BL/6 animals treated with 4-ABAH (mean survival of 23.8 days) compared to wild type animals. Taken together, these data demonstrated that MPO-expressing cells contribute to host protection during tumor initiation in a NF-κB-dependent manner.
Citation Format: Tracy W. Liu, Seth T. Gammon, David Piwnica-Worms. Innate immune cells expressing myeloperoxidase directly inhibit tumor NF-κB transcriptional activation during tumor initiation [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 3139.
Abstract 3143: A novel approach to deplete Treg cells using non-IL-2 blocking anti-CD25-targeting antibodies leads to complete rejection of established tumors
Authors: Solomon Isabelle , Vargas Frederick Arce , Zervas Dimitrios , Qing Chen , Salimu Josephine , Brown Mark , Merchiers Pascal , Boughetane Aghiles , Peggs Karl S. , Goubier Anne , Quezada Sergio A. 
Published: August 2018

Abstract
The accumulation of regulatory T cells (Tregs) in the tumor hampers effector anti-tumor activity and correlates with a bad prognosis in several human cancers. Increasing the effector T cell (Teff) to regulatory T cell (Treg) ratio is known to result in improved control of established tumors. Studies demonstrating high levels of CD25 expression on Tregs but not Teff in human tumors have underscored its relevance as a target for Treg depletion. This supported the development of anti-CD25 depleting monoclonal antibodies (mAbs) as a promising monotherapy as well as combination partner in cancer immunotherapies. To date, anti-CD25 antibodies for clinical use have been designed to deplete CD25 positive cells but also to block IL-2 binding and signaling. Since IL-2 is a critical cytokine involved in T cell activation and proliferation, we hypothesized that a depleting antibody targeting CD25 on Treg cells but not blocking IL-2 signaling on Teff cells would induce a more potent anti-tumor response by depleting Tregs whilst still allowing IL-2 to stimulate effector T cells. We therefore compared the functional activity of anti-mouse CD25 depleting mAbs with and without IL-2 blocking activity. After having confirmed their differential impact on IL-2 signaling, we evaluated the therapeutic activity of these mAbs in various syngeneic tumor models. While both the IL-2 blocking and non-IL-2 blocking mAbs showed equivalent Treg-depleting activity, the antibody sparing IL-2 signaling promoted stronger anti-tumor effect than the IL-2 blocking mAb, with complete tumor regression observed in 70-100% of the mice after a single administration of the antibody. Our data demonstrates that targeting CD25 with ADCC enabled antibodies preserving IL-2 signaling is a novel and powerful strategy for rejection of established tumors via depletion of Treg cells and enhanced, cell intrinsic, IL-2-driven effector T cell activation.
Citation Format: Isabelle Solomon, Frederick Arce Vargas, Dimitrios Zervas, Chen Qing, Josephine Salimu, Mark Brown, Pascal Merchiers, Aghiles Boughetane, Karl S. Peggs, Anne Goubier, Sergio A. Quezada. A novel approach to deplete Treg cells using non-IL-2 blocking anti-CD25-targeting antibodies leads to complete rejection of established tumors [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 3143.
Abstract 3145: Characterization of novel immune checkpoint receptors within the breast cancer tumor microenvironment
Authors: Williams Austin D. , Campbell Jean S. , Aicher Lauri D. , Payne Kyle K. , Conejo-Garcia Jose R. , Pierce Robert H. , Tchou Julia 
Published: August 2018

Abstract
Introduction. The interruption of immune checkpoint receptor (ICR)/ligand interaction within the tumor microenvironment has become an important immunotherapy strategy. In breast cancer (BC), neither the ICR phenotype of immune cells of each BC subtype nor the associated immune response is fully characterized. We hypothesize that there are differences in ICR phenotypes between BC subtypes. Methods. To analyze the expression of ICRs (i.e. PDCD1 (PD-1), TIGIT, HAVCR2 (Tim-3), and LAG3 in the tumor microenvironment (TME) of BC, the 956- patient BC cohort of The Cancer Genome Atlas (TCGA) gene expression data was analyzed and normalized against CD3E, a T-cell specific transcript. As validation, we examined various ICR by flow cytometry on 14 matched dissociated breast tumor and peripheral blood mononuclear cells (PBMC) and compared differences across BC subtypes with t-test and ANOVA. In addition, differential gene expression and multispectral analysis were investigated using FFPE specimens and the NanoString and Vectra platforms. Results. TCGA data revealed a higher expression of TIGIT, LAG3 and PD-1 in triple-negative breast cancer (TNBC) when compared to other subtypes (p &lt;0.001, Table 1). PD-L1 (CD274) expression was higher in TNBC than ER/PR+/Her2- cancer (p=-0.008). On flow cytometry, there was a higher co-expression of TIGIT and Tim-3 on CD4 T cells in TNBC than all other subtypes (p=0.003) while ER/PR+Her2- cancers had the highest CD4 expression of TIGIT alone (p=0.04). Compared to ER/PR+Her2- cancers, TNBC had increased expression of transcripts associated with myeloid derived suppressor cells, and decreased expression of transcription factors that regulate lineage specification for CD4 helper T cells. Conclusions. In addition to PD-1, we demonstrated that other ICRs may play significant roles in TME of Her2+ and TNBC BC subtypes. Our results support the development of novel anti-ICR therapy which may synergize with current treatment strategies against these unfavorable BC subtypes.
Citation Format: Austin D. Williams, Jean S. Campbell, Lauri D. Aicher, Kyle K. Payne, Jose R. Conejo-Garcia, Robert H. Pierce, Julia Tchou. Characterization of novel immune checkpoint receptors within the breast cancer tumor microenvironment [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 3145.
Abstract 3149: Collagen XIII induces β1-integrin activation and triple-negative breast cancer metastasis
Authors: Zhang Hui , Fredericks Tricia , Xu Ren 
Published: August 2018

Abstract
Increased collagen expression and deposition is a risk factor for breast cancer development. Collagen XIII is a type II transmembrane protein within the collagen superfamily. Experiments in tissue culture and knockout mouse model show that collagen XIII is involved in cell adhesion and differentiation of certain cell types. However, function of collagen XIII in cancer development and progression largely remains to be determined. We found that collagen XIII expression is significantly induced during breast cancer development, especially in triple negative breast cancer. Increased collagen XIII mRNA level is associated with poor prognosis. Importantly, silencing collagen XIII expression in MDA MB 231 cells slow down xenograft growth and significantly reduced cancer metastasis in mice. Using gain- and loss-of function approaches, we showed that collagen XIII enhanced cell migration, invasion, and mammosphere/tumorsphere formation. We also found that collagen XIII induced integrin-β1 activation, and subsequently enhanced TGF-β signaling. Blocking integrin-β1 activation with AIIB2 antibody significantly reduced collagen XIII-induced cell migration and mammosphere formation. These findings demonstrate a novel function of collagen XIII in promoting cancer metastasis through enhancing β1 integrin-dependent cell migration and invasion
Citation Format: Hui Zhang, Tricia Fredericks, Ren Xu. Collagen XIII induces β1-integrin activation and triple-negative breast cancer metastasis [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 3149.