bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract PR14: HIF-2alpha regulates self-renewal of MYC dependent cancer stem cells
Authors: Das Bikul , Das Bikul , Li Hong , Li Hong , Bhuyan Rashmi , Felsher Dean W. 
Published: October 2015

Abstract
Numerous studies report that both hematopoietic and some solid tumors are organized in a hierarchical manner where tumor growth is driven by a small subset of cancer stem cells (CSCs). However, the distinct molecular identity of CSC versus non-CSC is not yet clearly known, which limit our understanding on how CSC self-renewal pathways operate to drive tumorigenicity. Here, we report that MYC and HIF-2alpha co-operate to maintain distinct identity and self-renewal capacity of CSCs. In a transgenic mouse model of conditional MYC driven thymic lymphoma, we identified a Sca-1+ cell population that showed tumor stemness (self-renewal and undifferentiation state) phenotype, including high expression of Nanog, Sox2 and HIF-2alpha. When injected to congenic mice, Sca-1+ cells but not Sca-1- cells exhibited hierarchical organization including self-renewal capacity. ChIP assay revealed direct MYC binding of HIF-2alpha promoter region in Sca-1+ but not in the Sca-1- cells. Inhibition of HIF-2alpha led to increase ROS generation, decrease of GSH synthesis, differentiation, and loss of self-renewal capacity of Sca-1+ cells. In contrast, inhibition of HIF-2alpha had no phenotypic effect on Sca-1- cells. Thus, we have identified a distinct CSC population in MYC dependent cancer cells, where MYC preferentially binds to HIF-2alpha to maintain self-renewal capacity.
Citation Format: Bikul Das, Bikul Das, Hong Li, Hong Li, Rashmi Bhuyan, Dean W. Felsher. HIF-2alpha regulates self-renewal of MYC dependent cancer stem cells. [abstract]. In: Proceedings of the AACR Special Conference on Myc: From Biology to Therapy; Jan 7-10, 2015; La Jolla, CA. Philadelphia (PA): AACR; Mol Cancer Res 2015;13(10 Suppl):Abstract nr PR14.
Abstract A04: Systemic agonistic anti-CD40 treatment of tumor bearing mice modulates hepatic myeloid suppressive cells and causes immune-mediated liver damage
Authors: Medina-Echeverz Jose , Ma Chi , Eggert Tobias , Greten Tim F. 
Published: October 2015

Abstract
Immune stimulatory monoclonal antibodies are currently evaluated as antitumor agents in clinical trials. Although overall toxicity appears to be moderate, liver toxicities have been reported and are not completely understood. Therefore, we decided to study the effect of systemic CD40 antibody treatment on the liver immune microenvironment. Agonistic CD40 antibody or isotype control was injected intraperitoneally into naïve and tumor-bearing mice. Liver enzymes, histologies and immune infiltrates were analyzed after antibody administration. The effect of agonistic CD40 administration was evaluated using bone marrow chimeras and genetically modified mouse strains Cd40-/- and Nox2-/-. Mouse and human tumor-induced myeloid suppressive cells were cultured to address changes in their immune function upon CD40 ligation. Agonistic CD40 antibody caused liver damage within 24 hours after injection in two unrelated tumor models and mice strains. Using bone marrow chimeras we could demonstrate that CD40 antibody-induced hepatitis in tumor-bearing mice was dependent on the presence of CD40+ immune cells. Agonistic CD40 ligation-dependent liver damage was induced by the generation of reactive oxygen species. Furthermore, agonistic CD40 antibody resulted in increased CD80 and CD40 positive liver CD11b+Gr-1+ immature myeloid cells. CD40 ligation on tumor-induced hepatic myeloid cells or CD14+HLA-DRlow PBMC from cancer patients reduced their immune suppressor function. Collectively, agonistic CD40 antibody activates the tumor-induced liver myeloid suppressive compartment, enhancing acute inflammation and thus liver damage. Our data in murine and human myeloid suppressive cells point towards a pivotal role for CD40 as a key molecule in modulating myeloid suppressive cell plasticity.
Citation Format: Jose Medina-Echeverz, Chi Ma, Tobias Eggert, Tim F. Greten. Systemic agonistic anti-CD40 treatment of tumor bearing mice modulates hepatic myeloid suppressive cells and causes immune-mediated liver damage. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr A04.
Abstract A28: TRAIL mediated reduction of an immunogenic cell death protein, heat shock protein 70, in glioblastoma
Authors: McCray Andrea N. 
Published: October 2015

Abstract
There are various Damage-Associated Molecular Patterns (DAMPs) that are recognizable by the immune system in the cancer microenvironment. DAMPs are revealed under a specific type of cell death termed immunogenic cell death in which stimuli force the cancer cells to die and leave antigen traces such as heat shock proteins that can be used against the disease. The stimulus of interest in this study was recombinant human Tumor-necrosis factor-related apoptosis-inducing ligand (TRAIL) which was known to selectively kill cancer cells such as glioblastoma cells. This study examined the role of TRAIL in immunogenic cell death for brain cancer. High density T98G glioblastoma cells were cultured with or without 50 ng/ml recombinant human TRAIL for four days. The trypan blue exclusion assay revealed that the average death rate for the TRAIL treated glioblastoma cells was 42%. Furthermore, western blot analysis showed that TRAIL treated cells had a reduction in heat shock protein 70 expression. Previous studies in the literature showed heat shock protein 70 mediated apoptosis resistance in cancer cells. The current study suggests that, even in the absence of any other inhibitors, heat shock protein 70 down-regulation via TRAIL may cause the chemoresistant glioblastoma cells to become susceptible to TRAIL-mediated cell death. Future studies will further investigate the relationship between DAMPs and TRAIL and the extent to which TRAIL generates sufficient apoptotic glioblastoma cells that would serve as the antigenic source for T cell immunotherapy regimens.
Disclaimer: This research was supported in part by the James A. Haley Veterans' Hospital. The contents of this publication do not represent the views of the Department of Veterans Affairs or the United States Government.
Citation Format: Andrea N. McCray. TRAIL mediated reduction of an immunogenic cell death protein, heat shock protein 70, in glioblastoma. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr A28.
Abstract A34: Characterization of tumor infiltrating lymphocytes in human breast cancer by infrared imaging
Authors: Verdonck Magali , Garaud Soizic , Buisseret Laurence , Duvillier Hugues , Desmedt Christine , Wind Roland de , Sotiriou Christos , Willard-Gallo Karen , Goormaghtigh Erik 
Published: October 2015

Abstract
In human breast cancer spatially organized Tumor Infiltrating Lymphocytes (TILs) have been associated with effective therapeutic responses and favorable clinical outcomes.[1-3] This study investigates the potential for using InfraRed (IR) imaging to identify and characterize infiltrating lymphocytes in breast tumors, focusing on CD4+, CD8+ T lymphocytes and B lymphocytes (CD20+). Fourier Transform InfraRed (FTIR) spectroscopy coupled with microscopy is an emerging tool in cancer research and diagnosis.[4,5] IR imaging can probe the chemical composition and molecular structure of cells and tissues, thereby providing a global and unique signature for all cellular constituents. Compared with standard techniques used for identification and characterization of immune cells in tissue sections, IR imaging has numerous advantages, including no requirement for staining or automation. In this study, infrared spectra of lymphocyte subpopulations were recorded for lymphocytes in FFPE tissue sections from tonsils and breast tumors. Samples were deposited on a BaF2 window and the spectroscopic imaging data acquired in transmission mode using a Hyperion imaging system (Bruker) equipped with a focal plane array detector. The specific lymphocyte subpopulations present in each region were evaluated using hematoxyline & eosin (HE) and immunofluorescent (IF) staining of adjacent tissue sections. Statistical analyses indicate that IR spectra obtained from the CD4+, CD8+ or CD20+ lymphocyte subpopulations in tonsils are significantly different and identifiable relative to the other subpopulations. These data suggest that FTIR imaging can be used to identify specific lymphocyte subpopulations in tissues based on their spectral features. Our current work is testing this hypothesis to examine immune infiltrates in breast tumor tissue and these data will be presented at the meeting.
[1] C. Gu-Trantien et al. 2013. J. Clin. Invest. 2013, 123(7) pp. 2873–2892.
[2] C. Gu-Trantien and K. Willard-Gallo. Oncoimmunol. 2013, 2(10):e26066.
[3] C. Denkert et al., J. Clin. Oncol. 2010, 28(1), pp. 105-113.
[4] G. Bellisola and C. Sorio, Am J. Cancer Res. 2012, 2(1), pp. 1-21.
[5] J. Nallala et al., Cytometry A. 2013, 83(3), pp. 294-300.
Citation Format: Magali Verdonck, Soizic Garaud, Laurence Buisseret, Hugues Duvillier, Christine Desmedt, Roland de Wind, Christos Sotiriou, Karen Willard-Gallo, Erik Goormaghtigh. Characterization of tumor infiltrating lymphocytes in human breast cancer by infrared imaging. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr A34.
Abstract A68: Local tumor treatments to simulate systemic antitumor immune responses
Authors: Lizotte Patrick , Sheen Mee Rie , Wen Amy M. , Steinmetz Nicole F. , Fiering Steven 
Published: October 2015

Abstract
The generation of effective systemic antitumor immune response is the central goal of tumor immunotherapy. The majority of efforts are focused on systemic treatments that inject therapeutic reagents IV. This is an excellent approach and will be a central facet of tumor immunotherapy, however there is also an opportunity to develop therapies that involve direct intratumoral treatments of recognized tumors with the goal of stimulating systemic antitumor immune responses. Such approach can be used in conjunction with systemically applied therapies and have advantages because of the greater ability to control reagent concentrations that are intratumorally injected. We will present data from recent studies that utilize attenuated microorganisms, known TLR agonists and hyperthermia alone or in combinations to treat murine melanoma and ovarian cancer.
Citation Format: Patrick Lizotte, Mee Rie Sheen, Amy M. Wen, Nicole F. Steinmetz, Steven Fiering. Local tumor treatments to simulate systemic antitumor immune responses. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr A68.
Abstract A69: The immunological environment in triple negative breast cancer; impact on clinical outcomes towards a prognostic clinical test
Authors: Gigoux Mathieu , Gruosso Tina , Bertos Nicholas , Saleh Sadiq , Omeroglu Atilla , Zhao Hong , Souleimanova Margarita , Meterissian Sarkis , Hallett Michael , Park Morag 
Published: October 2015

Abstract
It is now accepted that changes in the normal cells that constitute the tumor microenvironment (TME) play important roles in determining cancer progression and ultimate outcome. We and others have established that an immune signature, and more recently that the ability of CD8+ T cells to infiltrate the tumor bed, are correlated with good outcome in triple negative breast cancer. Importantly, since the cytotoxic effector functions of CD8+ T cells are mainly contact-dependent, the tumor microenvironment may act to inhibit access to the epithelial tumor bed, leading to uncontrolled tumor growth. Therefore, in order to determine the role that the TME plays on mediating the entry of CD8+ T cells into the epithelial tumor bed, our group performed laser-capture microdissection to separate the tumor epithelial compartment from the surrounding tumor-associated stroma from the primary tumor of 56 triple negative breast cancer patients and followed by gene expression profiling. Our aims are to provide clinical validation of predicted CD8+ T cell localisation based on our bioinformatic analysis, test our predictions that the identified stroma signature correlates with CD8+ T cell retention in other cohort of TN breast cancer patients and develop suitable markers of this stroma, and develop a muliplex based assay integrating CD8+ T cell localisation with stromal markers suitable for a retrospective study to validate predictions with outcome. Using gene expression profiling, our data have identified a canonical gene expression signature which correlates with retention of CD8+ T cells in the stroma and poor outcome. Thus, our results demonstrate that gene expression analysis of clinical triple negative breast cancer samples can predict the location of CD8+ T cells within the tumor and in turn the outcome.
Citation Format: Mathieu Gigoux, Tina Gruosso, Nicholas Bertos, Sadiq Saleh, Atilla Omeroglu, Hong Zhao, Margarita Souleimanova, Sarkis Meterissian, Michael Hallett, Morag Park. The immunological environment in triple negative breast cancer; impact on clinical outcomes towards a prognostic clinical test. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr A69.
Abstract A74: Spatial organization of myeloid cells in tumor microenvironment
Authors: Kim Minhyeok , Lee Seon Woo , Kang Suk-Jo , Kang Changwon 
Published: October 2015

Abstract
Myeloid cells infiltrating tumor microenvironment orchestrate immune response to induce cancer progression. From tumor cell proliferation to angiogenesis, invasion, and metastasis, every step of cancer development is controlled by distinct types of immune cells. Tumor-associated macrophages (TAMs), myeloid derived suppressor cells (MDSCs), TIE2-expressing monocytes (TEMs), tumor associated neutrophils (TANs), and sub-population of dendritic cells are examples of tumor promoting myeloid cells. These numerous types of myeloid cells have been identified and characterized but their spatial organization within the tumor microenvironment have not been analyzed thoroughly. To understand their actions and mechanisms on cancer promotion, understanding their organization is required. By using EL4 thymoma syngenic graft model, we analyzed composition of myeloid cells infiltrating EL4 tumor microenvironment and revealed spatial organization of each type of myeloid cells. Dozens of immune cell surface markers were used to comprehensively define and characterize tumor infiltrating myeloid cells. Most of CD11b positive myeloid cells were localized at surrounding matrix of tumor mass. In particular, immunosuppressive immune cells like MDSCs were localized surrounding matrix of tumor and barely infiltrating actual tumor mass. In contrast, TAMs and dendritic cells are integrated with tumor cells inside the tumor mass. Dendritic cells can be subdivided based on CD11b expression level and those two distinct subsets are localized at distinct area of tumor mass. This analysis of spatial localization of immune cells implies division of labor among the cancer promoting myeloid cells. Tumor mass integrated myeloid cells suspected to promote angiogenesis and tumor cell proliferation. Tumor surrounding matrix localized myeloid cells suspected to promote immune suppression, invasion and metastasis.
Citation Format: Minhyeok Kim, Seon Woo Lee, Suk-Jo Kang, Changwon Kang. Spatial organization of myeloid cells in tumor microenvironment. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr A74.
Abstract A92: Small molecules targeting HMGR and HDAC in colorectal cancer
Authors: Wei Tzu-Tang , Lin Yi-Ting , Lin Yu-Chin , Chen Ching-Chow 
Published: October 2015

Abstract
Background and Aims: Colorectal cancer (CRC) is an important cancer with rising annual incidence worldwide, leading to significant morbidity and mortality. The addition of new anti-CRC drugs significantly improves treatment outcome, indicating that it is crucial to develop new drugs. Chemoprevention is another important approach to reduce cancer-related mortality. We first demonstrated statins with a carboxylic acid-containing long chain inhibiting histone deacetylase (HDAC) activity. To further improve their HDAC inhibition, we designed and synthesized three statin hydroxamates (JMF3086, JMF3171 and JMF3173) that potently inhibit 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR) and histone deacetylases (HDACs) simultaneously. Their preventive and therapeutic effects on CRC were investigated.
Methods: The in vitro anticancer activity was evaluated in human cancer cells. Molecular mechanisms were investigated using genome-wide ChIP-on-chip, Gene Ontology (GO) and Ingenuity Pathway Analysis (IPA). Anti-inflammation was examined by Dextran sulfate sodium (DSS)-induced acute colitis in mice. Prevention or therapy for CRC was examined by AOM/DSS mouse model. Anti-metastasis was examined by splenic and tail vein injected mouse models, and colorectal cancer stem cells were generated to investigate the inhibition of stemness.
Results: Statin hydroxamates were effective to inhibit a variety of human cancer cells. ChIP-on-chip analysis demonstrated the down-regulation of inflammatory and stemness genes and up-regulation of tumor suppressor genes. GO and IPA predicted the regulatory role of NF-kB in inflammatory genes and NR3C1 in apoptosis-related genes. The oral administration of JMF3086 prevented DSS-induced colitis and AOM/DSS-induced CRC in mice by inhibiting inflammation. Statin hydroxamates exerted a therapeutic effect in CRC mice by inducing apoptosis. CRC metastasis to the livers and lungs and the propagation of CRC stem cells in vivo were also inhibited by JMF3086. The efficacy of JMF3086 was superior to the combination of lovastatin and SAHA (HDAC inhibitor) with less toxicity.
Conclusions: Statin hydroxamates with dual inhibition on HMGR and HDACs show great preclinical efficacy in prevention and treatment of CRC through inhibiting inflammation and inducing apoptosis.
Citation Format: Tzu-Tang Wei, Yi-Ting Lin, Yu-Chin Lin, Ching-Chow Chen. Small molecules targeting HMGR and HDAC in colorectal cancer. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr A92.
Abstract B18: Adoptive T-cell transfer combined with murine cytokine-armed adenoviruses for the treatment of melanoma
Authors: Siurala Mikko , Havunen Riikka , Bramante Simona , Saha Dipongkor , Tähtinen Siri , Vähä-Koskela Markus , Hemminki Akseli 
Published: October 2015

Abstract
Adoptive cell transfer (ACT) has shown promising results in clinical trials for melanoma, with response rates ranging from 40% to 72%. We aimed to enhance the efficacy of ACT by coupling it with adenoviruses coding for immunostimulatory cytokines. The non-replicating adenoviruses that were constructed (Ad5-CMV-mIFNg, Ad5-CMV-mIL2, Ad5-CMV-mIFNb and Ad5-CMV-mTNFa) were confirmed to produce biologically active murine cytokines in vitro. These viruses were then used in combination with adoptive transfer of OT-1 TCR transgenic T-cells to treat C57BL/6 mice bearing B16-OVA melanoma tumors. The animals were administered intraperitoneally with 1.5 x 106 CD8+-enriched OT-1 cells with or without intratumoral injections of cytokine-coding adenoviruses (1 x 109 viral particles/tumor). Combination treatment with Ad5-CMV-mIL2 and OT-1 resulted in statistically significant antitumor efficacy when compared with either monotherapy and untreated control (combination vs. virus, p=0.026; combination vs. OT1, p=0.003; combination vs. mock, p&lt;0.001). Similar results were obtained with other cytokine-coding virus and OT-1 combinations, except for mIFNb. In further experiments a triple combination of Ad5-CMV-mIL2 + Ad5-CMV-mTNFa (1:1 ratio) and OT-1 T-cells were used to treat B16-OVA; improved antitumor efficacy was observed with the triple combination over dual agent therapies (triple combination vs. Ad5-CMV-mIL2 + OT-1, p=0.001; triple combination vs. Ad5-CMV-mTNFa + OT-1, p=0.049). In summary, these results support the further development of a novel immunotherapeutic approach for the treatment of melanoma.
Citation Format: Mikko Siurala, Riikka Havunen, Simona Bramante, Dipongkor Saha, Siri Tähtinen, Markus Vähä-Koskela, Akseli Hemminki. Adoptive T-cell transfer combined with murine cytokine-armed adenoviruses for the treatment of melanoma. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr B18.
Abstract B26: Translation of cancer vaccine strategies from mice to clinical trials
Authors: Berzofsky Jay A. , Terabe Masaki , Wood Lauren V. 
Published: October 2015

Abstract
We have developed several cancer vaccine strategies and translated them from mice to humans. We used “epitope enhancement” to modify an epitope of the TARP prostate cancer antigen to increase affinity for HLA-A2 and immunogenicity in HLA-A2-transgenic mice. This and another high affinity TARP epitope elicited human T cells killing human tumor cells. We translated these into a vaccine trial in stage D0 prostate cancer, in which patients after primary disease treatment have rising PSA. Patients received TARP peptides either in montanide or pulsed onto autologous DCs. No difference was seen between arms. 72% of vaccinees at 24 wks and 74% at 48 wks had a decreased PSA velocity (p= 0.0004), a validated measure of tumor growth. 77% of vaccinees made a specific IFNγ ELISpot response, but there was no correlation with clinical effect, suggesting that the quality of the T cells is critical. Accordingly, a phase II randomized placebo-controlled clinical trial is being opened. We also developed an adenovirus vaccine expressing the extracellular & transmembrane domains of HER2, which cured almost all mice with large (up to 2 cm) established tumors and lung metastases. The protection in mice is purely antibody-dependent. We translated this to a clinical trial with autologous DCs transduced with an adenovirus expressing human HER2 domains. The first part is a dose-escalation in patients with any type of cancer expressing 1+ to 3+ HER2 by IHC who are naïve to HER2-targeted therapies. In 1 of 2 patients so far at the 2nd dose level for which we have data, we have an indication of a partial response. Thus, translation of cancer vaccine strategies from mice to humans is beginning to show promising results.
Citation Format: Jay A. Berzofsky, Masaki Terabe, Lauren V. Wood. Translation of cancer vaccine strategies from mice to clinical trials. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr B26.