bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3636: Anti-CD20 therapy prevents protumor regulatory T-cell expansion and triggers a memory Th1 response in tumor-bearing mice
Authors: Deligne Claire , Siberil Sophie , Teillaud Jean-Luc 
Published: May 2015

Abstract
The long-lasting clinical response by lymphoma patients to anti-CD20 treatment has been attributed to a ‘vaccinal’-type effect through the induction of an anti-tumor adaptive immunity. Using a model where C57Bl/6 mice were injected intravenously with EL4 tumor cells expressing human CD20, we previously showed that CD4 cells are central to the host protection induced by anti-CD20 therapy. Here, we have first shown that the transfer of highly purified CD4+ T cells induces a long-term protection, demonstrating that this T-cell subset plays indeed a key role in the induction of an adaptive memory response. In addition, CD4+ effector memory T cells were detected in surviving animals. We have then analyzed the changes occurring in various T cell subsets in tumor-bearing animals receiving anti-CD20 treatment. On the one hand, untreated animals exhibited a large expansion of CD4+FoxP3+ regulatory T cells (Tregs), with reduced survival. Depletion of these cells using anti-CD25 injection led to long-term survival, indicating that a Treg-dependent immuno-suppressive environment is established after tumor injection in this model. On the other hand, anti-CD20 therapy, that induces a long-lasting protection, reversed the initial expansion of Tregs one week after the end of anti-CD20 treatment, and was accompanied by a marked increase in the number of Th1 cells. Concomitantly, an increase in the serum levels of interleukin-12 was observed, as well as an increased in the number of activated myeloid dendritic cells producing this cytokine. Moreover, a strong decrease in the survival was observed when Natural Killer cells were depleted using anti-asialo GM1 antibodies or following neutralization of interferon-γ. Thus, the host protection elicited by anti-CD20 treatment involves a network of cells from both innate and adaptive immunity that both are needed for long-term protection. In conclusion, our work demonstrates that anti-CD20 therapy promotes a strong anti-tumor adaptive immunity, opposes Treg expansion, and that a pro-tumor immune contexture shaped by the presence of growing tumor cells can be reversed by antibody treatment.
Citation Format: Claire Deligne, Sophie Siberil, Jean-Luc Teillaud. Anti-CD20 therapy prevents protumor regulatory T-cell expansion and triggers a memory Th1 response in tumor-bearing mice. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3636. doi:10.1158/1538-7445.AM2014-3636
Abstract 3656: MDSC-generated nitric oxide leads to an impairment of NK cell functions in metastatic melanoma patients
Authors: Trikha Prashant , Mundy-Bosse Bethany , Landi Ian , McMichael Elizabeth , Harper Amanda , Duggan Megan , Stasik Nancy , Kendra Kari , Olencki Thomas , Carson William 
Published: May 2015

Abstract
Myeloid-derived suppressor cells (MDSCs) are able to inhibit the function of immune cells within the tumor microenvironment. The interaction of MDSCs with T cells has been studied extensively. However, the interaction of MDSCs with innate immune cells such as NK cells is not well understood. This study investigated whether the presence of MDSCs could impair the function of NK cells.
MDSC (CD33+HLA-DRneg/lowCD11b+) and autologous NK cells (CD56+CD3neg) were isolated from the peripheral blood of metastatic melanoma patients and co-cultured overnight at a 1:1 ratio (2 x 105 cells each). Culture with MDSC led to a 70% decrease in NK cell mediated antibody dependent cellular cytotoxicity (ADCC) against HER2+ SkBr3 cells coated with an anti-HER2 antibody and a two-fold decrease in the production of interferon-gamma in response to these targets. Stimulation of the NK cell Fc receptor by immobilized immunoglobulin G (IgG) led to phosphorylation of Erk (p-Erk) and this event was significantly inhibited in the presence of MDSC in a dose and contact-dependent manner (p&lt;0.05). Co-culture of NK cells with MDSC also led to reduced expression of the NKp30 activating receptor (1.7-fold decrease) and a decrease in cytotoxicity against the K562 cell line. MDSC were able to generate significant levels of nitric oxide (NO) and inhibition of MDSC NO synthesis in co-cultures led to a significant improvement in NK cell cytotoxicity and cytokine production (p&lt;0.05). Depletion of MDSC from BALB/c mice bearing tumors of the CT26 adenocarcinoma cell line led to a three-fold increase in NK cell mediated ADCC. These results demonstrate that MDSC-derived NO can inhibit NK cell function, and suggest that strategies aimed at eliminating or deactivating MDSC may lead to enhanced efficacy of immune based therapies.
Citation Format: Prashant Trikha, Bethany Mundy-Bosse, Ian Landi, Elizabeth McMichael, Amanda Harper, Megan Duggan, Nancy Stasik, Kari Kendra, Thomas Olencki, William Carson. MDSC-generated nitric oxide leads to an impairment of NK cell functions in metastatic melanoma patients. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3656. doi:10.1158/1538-7445.AM2014-3656
Abstract 3660: Chronic alcohol consumption inhibits iNKT cell activation-induced antitumor response in B16BL6 melanoma-bearing mice
Authors: Zhang Hui , Zhang Faya , Zhu ZhaoHui , Meadows Gary G. 
Published: May 2015

Abstract
Alcohol consumption increases the incidence of many types of cancer including melanoma. It is not well understand how chronic alcohol consumption affects tumor progression and survival. We previously found that chronic alcohol consumption activates CD8+ T cells in the non-tumor injected mice and at the early stage after tumor inoculation; however, it accelerates CD8+T cell dysfunction during further tumor growth. The underlying mechanism regarding modulation of CD8+ T cells by alcohol and how the functional changes in the immune response affect tumor growth and survival remain to be elucidated. Herein, we investigated how alcohol modulates iNKT cells in melanoma-bearing mice and how different immune treatment regimens affect tumor growth and survival. We found that alcohol increases iNKT cells in non-tumor injected mice, and that activation of these iNKT cells induces a Th1 response. With tumor progression, alcohol reverses iNKT cell cytokine profile to aTh2-dominant one. Chronic alcohol consumption inhibits melanoma growth, but this is does associated with increased survival. Immunization with a melanoma cell lysate significantly inhibits tumor growth and increases survival compared to the non-immunized alcohol-consuming, tumor-bearing mice. Immunization in the water-drinking control mice did not significantly increase survival compared to respective non-immunized mice. Immunization coupled with iNKT cell activation with alpha GalCer significantly increases the survival of water-drinking melanoma-bearing mice. However, the survival of mice consuming alcohol was significantly decreased compared to their water-drinking counterparts. Collectively, chronic alcohol consumption interacting with melanoma alters the iNKT cell cytokine profile from Th1-dominant to Th2- dominant, which in turn contributes to inhibition of antitumor immunity and decreases survival of melanoma-bearing mice. Supported by NIH grants R01AA07293 and K05AA017149 and funds provided for medical and biological research by the State of Washington Initiative Measure No. 171.
Citation Format: Hui Zhang, Faya Zhang, ZhaoHui Zhu, Gary G. Meadows. Chronic alcohol consumption inhibits iNKT cell activation-induced antitumor response in B16BL6 melanoma-bearing mice. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3660. doi:10.1158/1538-7445.AM2014-3660
Abstract 3661: Crucial roles of cytokine-signaling for alteration in functions of myeloid-derived suppressor cells
Authors: Sumida Kentaro , Ono Yosuke , Ohtake Junya , Masuko Kazutaka , Terada Satoshi , Kaneumi Shun , Kishikawa Takuto , Kita Toshiyuki , Kitamura Hidemitsu 
Published: May 2015

Abstract
Various types of myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs) were generated from immature myeloid cells (ImCs) according to the state of tumor microenvironments. In human cancer patients, MDSCs are generally defined as monocytic (CD11b+, CD14+, and HLA-DR-/low) or granulocytic (CD11b+ and CD15+) myeloid cells with antitumor and immunosuppressive activities. In order to develop the effective cancer immunotherapy, these immune suppressor populations should be restrictlly controlled in tumor bearing hosts.
In the present research, we evaluated the immunological functions of monocytic or granulocytic myeloid cells, which were collected from tumor tissues of colorectal cancer patients. We found here that myeloid populations in tumor tissues significantly induced immuno-modulating factors such as IL-6, IL-10, VEGF, iNOS, ARG1, IDO1, and IDO2. In addition, we confirmed that tumor-infiltrating myeloid-populations exhibited a significant immunosuppressive activity than those prepared from peripheral blood mononuclear cells (PBMCs). To investigate how tumor-infiltrating MDSCs acquired the immunosuppressive activity, we focused on the effect of tumor-derived factors (TDFs) on immunosuppressive activity. PBMCs from healthy volunteers were cultured in the presence of IL-6, TGF-β, and granulocyte macrophage colony-stimulating factor (GM-CSF) for 6 days, and then differentiated into Mo-MDSCs (CD11b+CD14+CD33+)-like phenotype cells. The generated Mo-MDSCs were further isolated by using cell sorter system and cultured with donor matched T cells and stimulated with anti-CD3/CD28 beads for 3 days. As a result, we confirmed that T cell proliferation was significantly inhibited by the addition of Mo-MDSCs generated with IL-6, TGF-β and GM-CSF. On the other hand, these populations showed immunostimulating ability in the presence of IFN-g in vitro, suggesting the Mo-MDSCs might have multi-differencing potentials.
These results indicated that tumor-infiltrating MDSCs acquired stronger immunosuppressive activity by tumor-derived IL-6 and TGF-β, however the function might be altered in response to cytokine conditions. Thus, we concluded that IL-6 and TGF-β induced functional maturation of MDSCs in tumor microenvironments, suggesting promising targets to improve the immunological responses by immunotherapy for cancer patients.
Citation Format: Kentaro Sumida, Yosuke Ono, Junya Ohtake, Kazutaka Masuko, Satoshi Terada, Shun Kaneumi, Takuto Kishikawa, Toshiyuki Kita, Hidemitsu Kitamura. Crucial roles of cytokine-signaling for alteration in functions of myeloid-derived suppressor cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3661. doi:10.1158/1538-7445.AM2014-3661
Abstract 367: Tumorigenesis: an investigation by network evolution and perturbations of somatic mutations in cancer interactome
Authors: Cheng Feixiong , Jia Peilin , Wang Quan , Lin Chen-Ching , Zhao Zhongming 
Published: May 2015

Abstract
Cells govern biological actions through highly complex biological networks. Perturbations to the complex molecular network due to driver mutations may transit cells to new phenotypic states, e.g., tumorigenesis. Identifying how genetic lesions such as somatic mutations perturb these networks is a fundamental challenge in cancer biology. The recent TCGA studies revealed that a typical tumor contains two to as many as eight of driver mutations while the numerous remaining somatic mutations are passenger mutations. So far, it remains largely unknown what evolutionary forces and how the genetic lesions disrupt cancer interactome that leads to tumorigenesis. In this study, we systematically investigated the relationship among the network topology, evolutionary rates, and evolutionary origins of somatic and germline mutation driven disease genes in the large context of the protein-protein interaction (PPI) networks by utilizing recently released extensive somatic mutations and gene annotation data. We aimed to address two fundamental questions. (1) Whether cancer genes display a distinct network topology from Mendelian disease genes, and why? (2) From a network biology perspective, how the transition occurs from a normal cell to a tumor cell as initiated by a few driver genetic mutations? We collected the largest ever cancer gene list and five comprehensive networks. We found evolutionary origin is the main determinant of the unique network centrality of cancer proteins. We further investigated the perturbations of network topology by somatic mutations that were identified from 3268 tumors across 12 cancer types in TCGA. We revealed that the network-attacking perturbation of somatic mutations on central hubs of cancer interactome is a main feature of tumor emergence and evolution. This finding elucidates the high efficiency of the transition during tumorigenesis as initiated by a few driver mutations. This work improves our understanding of dynamic network-attacking perturbation by somatic mutations during tumorigenesis, and, in turn, of the implications for both basic cancer biology and the development of personalized antitumor therapy.
Citation Format: Feixiong Cheng, Peilin Jia, Quan Wang, Chen-Ching Lin, Zhongming Zhao. Tumorigenesis: an investigation by network evolution and perturbations of somatic mutations in cancer interactome. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 367. doi:10.1158/1538-7445.AM2014-367
Abstract 3676: Influence of early toxicology assessment on the selection of azd9291
Authors: Anderton Mark J. , Ward Richard A. , Daunt Paula , Galer Anne , Cross Darren A. E. , Marks Louise , Finlay M. Raymond V. 
Published: May 2015

Abstract
Discovery toxicology is the concept of evaluating the safety of molecules early in the drug development process when there is chemical scope to refine candidate drug quality. The aim is to identify and mitigate safety liabilities to maximize the chance of clinical success. This poster describes the impact of discovery toxicology on the selection of AZD9291, an irreversible inhibitor of both EGFR-TKI sensitising and resistance mutations. Although, maintaining a margin of selectivity to wild type EGFR was a key medicinal chemistry goal, early in vitro selectivity evaluation of the lead series compounds revealed significant off-target inhibition against the insulin and insulin-like growth factor receptors (IR/IGFR). Further exploration of this liability in a rat in vivo study revealed that our early lead compound (Cmpd 1) was associated with severe hyperglycemia, rapid body weight loss and evidence of reduced gastric emptying. The reduction in bodyweight and the inhibition of gastric emptying was dose limiting and we hypothesized this was caused by the hyperglycaemia. A broader selection of compounds based on the same scaffold was tested both in vitro and in vivo in the hope of identifying one or more compounds without this liability. Compounds were tested in a modified single dose rat study, exploring insulin and glucose homeostasis and effects on gastric emptying. Compounds within the shortlist caused increases in insulin of up to 80-fold, 3-fold increases in glucose and up to a 60% reduction in gastric emptying. There was a clear link between in vitro IR/IGF inhibition, hyperinsulinemia and inhibition of gastric emptying. One of the shortlisted candidates (now selected as AZD9291), had up to a 30 fold improvement in in vitro IGFR cellular potency compared to previous candidates and had no effect on insulin/glucose homeostasis in vivo. AZD9291 has demonstrated tumor shrinkage in patients at doses that have been very well tolerated and to date, no effect on glucose homeostasis has been reported.
Cmpd 1Cmpd 2Cmpd 3Cmpd 4Cmpd 5 (AZD9291)EGFRm+sensitising mutationcell IC50 (pEGF μM)0.390.0160.0210.0020.017EGFRm+/T790Mdouble mutationcell IC50 (pEGF μM)0.0910.0020.0040.00070.015EGFR wildtypecell IC50 (pEGF μM)23.00.360.940.150.48IGFRcell IC50 (pIGF μM)0.0990.160.490.103.3SM/IGFR selectivity0.25102348194
Citation Format: Mark J. Anderton, Richard A. Ward, Paula Daunt, Anne Galer, Darren A. E. Cross, Louise Marks, M. Raymond V. Finlay. Influence of early toxicology assessment on the selection of azd9291. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3676. doi:10.1158/1538-7445.AM2014-3676
Abstract 3679: Inhibition of LSD1 disrupts global EWS/ETS transcriptional function in Ewing sarcoma
Authors: Theisen Emily Rose , Sankar Savita , Bearss Jared , Mulvihill Timothy , Sorna Venkataswamy , Sharma Sunil , Lessnick Stephen L. 
Published: May 2015

Abstract
Ewing sarcoma is an aggressive pediatric bone tumor characterized by an absolute reliance on the transcriptional activity of the EWS/ETS family of transcription factor fusion oncoproteins. The most common fusion is EWS/FLI, present in 85-95% of cases, though less common fusions include EWS/ERG, EWS/ETV1, EWS/ETV4 and EWS/FEV. EWS/FLI utilizes lysine-specific demethylase 1 (LSD1) as member of the NuRD complex to mediate transcriptional repression of critical tumor suppressors in Ewing sarcoma. LSD1 overexpression has been observed in clinical samples from Ewing sarcoma patients and small molecule blockade of LSD1 using tranylcypromine has been suggested as a therapeutic approach for Ewing sarcoma. We therefore evaluated the effects of LSD1 inhibition with the small molecule inhibitor, HCI-2509, in both in vitro and in vivo models of Ewing sarcoma. HCI-2509 is an LSD1 inhibitor with a Ki of ∼30 nM and multiple Ewing sarcoma cell lines show IC50s in cell viability assays from 500 nM-1 μM. Using RNA-seq, we show that HCI-2509 dramatically reverses both the up- and downregulated transcriptional profiles of both EWS/FLI and EWS/ERG accompanied by the induction of apoptosis and disruption of oncogenic phenotypes modulated by EWS/FLI. We further developed a 9-gene panel based on the RNA-seq data to assess the transcriptional phenotype of HCI-2509 in additional cell lines and showed that it HCI-2509 disrupted both EWS/FLI-activated and -repressed genes similarly across the tested Ewing sarcoma cell lines. HCI-2509 impaired transformation of Ewing sarcoma cell lines in colony forming assays with IC50s from from 25 nM-1 μM. Notably, HCI-2509 displayed single-agent efficacy in multiple xenograft models. We investigated the PK/PD relationship using tumor histone H3K4 and H3K9 methylation. Taken together, these data suggest that epigenetic modulation through LSD1 inhibition may be a therapeutic strategy for Ewing sarcoma, and highlight a critical dual role for LSD1 in the oncogenic transcriptional activity of EWS/ETS proteins.
Citation Format: Emily Rose Theisen, Savita Sankar, Jared Bearss, Timothy Mulvihill, Venkataswamy Sorna, Sunil Sharma, Stephen L. Lessnick. Inhibition of LSD1 disrupts global EWS/ETS transcriptional function in Ewing sarcoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3679. doi:10.1158/1538-7445.AM2014-3679
Abstract 3698: Hyperactive AKT pathway and reactivation of the MAPK/ERK pathway in melanoma cells resistant to dual BRAF and MEK inhibition
Authors: Wang Victoria E. , McCormick Frank , Settleman Jeffrey 
Published: May 2015

Abstract
In order to understand the mechanisms of resistance in melanoma cells treated with dual BRAF and MEK inhibitors, A375 and SK-Mel-28 cell lines, both harboring the BRAF V600E mutation, were treated with escalating doses of vemurafenib and cobimetinib to generate dual resistant lines. Resulting cells demonstrated 10 to 30 fold increase in resistance to the drug combination compared with the parental lines. The resistance phenotype could not be reversed by an ERK inhibitor. RNA sequencing and Western analyses revealed hyperactivation of the PI3K-AKT pathway in the A375 dual resistant cells. These cells may be re-sensitized with either a pan-PI3K inhibitor or PI3K/mTOR inhibitor. The SK-Mel-28 cells have constitutively active PI3K/AKT pathways at baseline and thus demonstrate reactivation of the MAP/ERK pathway in dual resistant cells. The therapeutic implications of these findings will be discussed.
Citation Format: Victoria E. Wang, Frank McCormick, Jeffrey Settleman. Hyperactive AKT pathway and reactivation of the MAPK/ERK pathway in melanoma cells resistant to dual BRAF and MEK inhibition. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3698. doi:10.1158/1538-7445.AM2014-3698
Abstract 370: Modeling signaling networks in tumor immunology
Authors: Clancy Trevor , Hovig Eivind 
Published: May 2015

Abstract
Despite decades of successful discoveries, the overwhelming molecular complexity of cells has been a significant barrier to gain a fundamental understanding of how cells work as a whole, how they are perturbed in cancer, and how they interact with signals from the immune system. To achieve a more complete understanding, will require the assistance of network modeling. By developing computational network models we can introduce cancer mutations to simulate pharmacological perturbations, or loss-of-function and gain-of-function experiments and study the dynamics of biochemical networks change under different immune signaling states. We are developing and applying rule-base (kappa) network modeling of signaling networks to study how microenvironment immune factors influence a tumor's behavior. In particular, that of immune mediated cellular senescence in tumor cells. We have built a rule-base network model of the biochemical network regulating immune mediated cell senescence in melanomas, which carry a BRAFV600 mutation in the MAPK signaling network. Using computational methods we have characterized the crosstalk with cytokine signaling networks and the crosstalk with other growth signaling networks. The development of such a computational model may help researchers understand how BRAFV600 cells in melanomas communicate with their environment by secreting various cytokines and growth factors, as it has become clear that this immune ‘secretory phenotype’ can have pro- as well as anti-tumorigenic effects.
By combining rule-based descriptions of the biochemical reactions associated to this phenotype with computer simulation we can open up new avenues for exploring such complex networks linked to melanoma progression.
Citation Format: Trevor Clancy, Eivind Hovig. Modeling signaling networks in tumor immunology. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 370. doi:10.1158/1538-7445.AM2014-370