bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4570: Selective depletion of regulatory T cells suppressed neuroblastoma tumor growth in mice
Authors: Lenthe Sophie von , Weißenborn Christine , Zenclussen Ana Claudia , Fest Stefan , Metelitsa Leonid 
Published: August 2019

Abstract
Purpose of the study
Neuroblastoma (NB) is the most common solid extracranial tumor in childhood. Regulatory T cells (Treg) are known to have immune suppressive capacity and to be involved in tolerance establishment. As they support tumor growth and help some tumors to overcome recognition by the host, they are considered to be an important target. Treg are reportedly increased in blood of NB patients. However, there are no scientific proofs to date that they are involved in neuroblastoma growth. To address this important question we employed Foxp3-DTR mice to selectively deplete Treg upon orthotopic application of syngeneic neuroblastoma cells.
Methods
Orthotopic NB tumors were generated in mice Foxp3-DTR mice and in C57Bl/6J controls by subcapsular tumor cell injection of NB975A cells into the left kidney. Primary tumor growth was analysed for 23 days by high frequency ultrasound measurement. To deplete Treg, InjectionDepletion of Diphtheria Toxin (DT, 15 ng/g bodyweight) intraperitoneally every 4 days in Foxp3.DTR mice depleted the Treg pool. Control Foxp3.DTR animals received PBS and control C57B/l6 received DT. All mice were sacrificed 23 days after tumor inoculation. Tumor as wells as immune cells harvested from spleen and inguinal lymph nodes were analyzed by Flow Cytometry, Immunofluorescenceimmunohistochemistry and qRT-PCR.
Results
In control mice bearing tumors, Treg presence was confirmed at the contact zone between the kidney and the growing, inoculated tumor.
Mice devoid of Treg (Foxp3-DTR+DT) showed a significantly reduced tumor growth compared to animals with normal Treg frequencies (Foxp3-DTR+PBS). Tumor growth in wild type controls was not affected by the application of DTR.
Conclusion
Ablation of Treg hindered the growth of NB, strongly suggesting their potential as therapeutic target for this aggressive childhood tumor.
Citation Format: Sophie von Lenthe, Christine Weißenborn, Ana Claudia Zenclussen, Stefan Fest, Leonid Metelitsa. Selective depletion of regulatory T cells suppressed neuroblastoma tumor growth in mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4570.
Abstract 4575: IL17 signaling modulates tumor microenvironment in pancreatic cancer
Authors: Zhang Yu , Sanchez Erick Marcelo Riquelme , Zoltan Michelle Annabel , McAllister Florencia 
Published: August 2019

Abstract
Pancreatic cancer is the one of the most devastating malignancies and the 5-years survival remains below 10% for decades. The pancreatic tumor microenvironment is very complex with tumor cells surrounded by a dense fibro-inflammatory stroma with fibroblasts and immune-suppressive cells which are known to play a pivotal role in the whole process of tumorigenesis, and contributing to the lack of responses to most therapies. We have previously described that IL17, a cytokine secreted from immune cells recruited to the pancreas in response to Kras and inflammation, is involved in the initiation and development of pancreatic premalignant lesions, in part by promoting stemness on the oncogenic epithelium. In this study, we aim to dissect the role of IL17 on the stroma in established pancreatic adenocarcinoma. To this end, we blocked the IL17 signaling pathway with monoclonal antibodies and also used a parallel genetic approach which consisted in IL17RA deletion from the cancer cells using CRISPR-Cas9. RNA sequencing analysis, flow cytometry, immunohistochemistry, and opal-multiplex immunofluorescence were performed on tumors and cellular compartments. We uncovered that neutrophils recruitment was the main pathway altered by IL-17. Using flow cytometry, IHC and opal-multiplex we found that Gr1+ cells were significantly modulated by Il17 in the tumor microenvironment, as not only the numbers of these cells were altered but also their spatial distribution with respect to CD8+T cells, which may contribute to the generation and maintenance of the immunosuppressive microenvironment that characterizes pancreatic cancer. Moreover, we found that reactive oxygen species (ROS) level was also evidently downregulated by IL17 signaling blockage.Therefore, we conclude that IL17 plays an important role in remodeling the pancreatic cancer immunosuppressive tumor microenvironment.
Citation Format: Yu Zhang, Erick Marcelo Riquelme Sanchez, Michelle Annabel Zoltan, Florencia McAllister. IL17 signaling modulates tumor microenvironment in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4575.
Abstract 4586: PLAG enhances macrophage mobility for efferocytosis of active neutrophils via membrane redistribution of P2Y2
Authors: Kim Guen Tae , Lee Do Young , Sohn Ki-young , Yoon Sun Young , Kim Jae Wha 
Published: August 2019

Abstract
Neutrophil activity is prerequisite during chemotherapy. The DAMP (Damage Associated Molecular Pattern) molecules generated by chemotherapy could be effectively trapped by activated neutrophil called ‘NETosis’. Efferocytosis of macrophages should remove most activated neutrophils including NETosis A timely removal of activated neutrophils is essential for the prevention of abnormal activation of immune response and metastatic activity of cancer cells induced by tumor microenvironment (TME). Particularly, appropriate clearance of the activated neutrophils by efferocytosis should be carried out because activated neutrophils have a detrimental effect on TME. In this research, we investigated the effect of 1-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol (PLAG) on efferocytosis and its underlying molecular mechanisms. In a co-culture of activated neutrophils with macrophages, PLAG increased the activity of efferocytosis for elimination of activated neutrophils. PLAG accelerated translocation of P2Y2 from lipid rafts to non-lipid-raft plasma membrane domains in macrophages. This repositioning of P2Y2 enables the polarization of the cytoskeleton by association of the receptor with cytoskeletal proteins such as α-tubulin and actin to improve the mobility of macrophages. Through these protein assemble, PLAG encouraged macrophage mobility toward the activated neutrophils. Formation of micelle including PLAG, chylomicron-like structures, was a prerequisite for induction of this macrophage activity. PLAG effect on this activity was not observed in the absence of GPIHBP1, micelle receptor. Taken together, these data showed that PLAG triggered a prompt clearance of activated neutrophils through enhancement of efferocytosis activity. Subsequently, PLAG could have effects on modulation of TME. PLAG could be utilized as an effective lipid-based TME modulator via the prevention of abnormal activation induced by uncontrolled immune response during chemotherapy.
Citation Format: Guen Tae Kim, Do Young Lee, Ki-young Sohn, Sun Young Yoon, Jae Wha Kim. PLAG enhances macrophage mobility for efferocytosis of active neutrophils via membrane redistribution of P2Y2 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4586.
Abstract 4587: The N-terminal domain of HARS is a novel NRP2 ligand and can regulate NRP2-dependent macrophage function
Authors: Sharma Navatha Shree , Dutta Samikshan , Crampton Steve , Rosengren Sanna , Datta Kaustubh 
Published: August 2019

Abstract
Tumor-associated macrophages (TAM) are associated with regulation of antitumor immune responses, and neuropilin-2 (NRP2), a pleiotropic receptor with an emerging role in immune responses, has recently been demonstrated to be important for this activity (Roy et al, Cancer Res. 2018). Deletion of NRP2 results in impaired clearance of apoptotic tumor cells through reduced efferocytosis, which plays a role in tumor promotion. We now show that the N-terminal domain of the histidyl-tRNA synthetase (HARS) is a specific binding partner of NRP2, and can regulate the phagocytic function of NRP2 in macrophages. The HARS N-terminal domain, which is found only in higher eukaryotes, is conserved among splice variants of HARS and has evolved to regulate immune cell engagement. Incubation of macrophages with recombinant HARS N-terminal domain, had no effect on phagocytic uptake, but significantly impaired the maturation of phagosomes in a dose dependent manner. This phenotype mimics that of the NRP2 knockout, suggesting pharmacological intervention with this agent to modulate NRP2 driven biology may be possible.
Citation Format: Navatha Shree Sharma, Samikshan Dutta, Steve Crampton, Sanna Rosengren, Kaustubh Datta. The N-terminal domain of HARS is a novel NRP2 ligand and can regulate NRP2-dependent macrophage function [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4587.
Abstract 4598: mTORC2 suppresses GSK3-dependent, but b-TrCP-independent, Snail degradation, contributing to positive regulation of cancer cell invasion and metastasis
Authors: Zhang Shuo , Qian Guoqing , Zhang Qian-Qian , Yao Yuying , Wang DongSheng , Chen Zhuo G. , Wang Lijing , Chen Mingwei , Sun Shi-Yong 
Published: August 2019

Abstract
Mammalian target of rapamycin (mTOR) complex 1 (mTORC1) positively regulates cell invasion and metastasis via enhancing Snail protein translation. The connection between mTOR complex 2 (mTORC2) and cell invasion and metastasis has also been suggested. However the underlying biology or mechanism is largely unknown and thus is the focus of this study. Inhibition of mTOR with both mTOR inhibitors and knockdown of the key components including rictor, Sin1 and raptor of mTORCs decreased Snail protein levels. mTOR inhibitors promoted Snail degradation rate. Moreover, mTOR inhibitor-induced Snail reduction was rescued by proteasome inhibition. Critically, inhibition of mTORC2 (by knocking down rictor), but not mTORC1 (by knocking down raptor), enhanced Snail degradation. Therefore, it is the inhibition of the mTORC2 that induces Snail proteasomal degradation, resulting in eventual Snail reduction. Interestingly, inhibition of GSK3, but not SCF/β-TrCP, rescued Snail reduction induced by mTOR inhibitors, suggesting a GSK3-dependent, but SCF/β-TrCP-independent proteasomal degradation of Snail. Accordingly, mTOR inhibitors elevated E-Cad levels and suppressed cancer cell migration and invasion in vitro and metastasis in vivo. Collectively, the current study has revealed a novel connection between mTORC2 and positive regulation of Snail stability, thus providing a scientific base for mTORC2 in positive regulation of cell EMT, invasion and metastasis. (This study was supported by NIH/NCI R01 CA118450 and CA160522 to SYS and National Natural Science Foundation of China No. 31771578 to QQZ).
Citation Format: Shuo Zhang, Guoqing Qian, Qian-Qian Zhang, Yuying Yao, DongSheng Wang, Zhuo G. Chen, Lijing Wang, Mingwei Chen, Shi-Yong Sun. mTORC2 suppresses GSK3-dependent, but b-TrCP-independent, Snail degradation, contributing to positive regulation of cancer cell invasion and metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4598.
Abstract 4600: IL-22 is specifically required for malignancy in breast cancer: A potential target to control cancer metastasis
Authors: Katara Gajendra K. , Kulshrestha Arpita , Schneiderman Sylvia , Ibrahim Safaa , Bilal Mahmood , Riehl Valerie E. , Beaman Kenneth D. 
Published: August 2019

Abstract
IL-22 is important for proliferation and progression of various epithelial cancers. However, in breast cancer, the current knowledge of IL-22 function is based on cell line models and lacks information on stage-specific involvement of IL-22 in multistage pathogenesis of disease. Here, we investigated whether IL-22 expression in the tumor microenvironment (TME) is a stage-specific requirement and if its inhibition can affect that specific stage of cancer progression. We show that the absence of IL-22 in TME did not hinder the initiation and proliferation of cancer but inhibited the invasion and metastasis of cancer. The influence of IL-22 on hyperplasia, adenoma, early carcinoma and late carcinoma stages of cancer was investigated using IL-22-/-/MMTV-PyMT spontaneous breast cancer mouse model. IL-22 levels were evaluated at these stages of cancer progression and validated in stage-specific specimens of human breast cancer. A variety of histopathological, in vivo and in vitroproliferation, migration, invasion and gene expression assays were performed on tumor tissues and purified epithelial cells. Results showed that IL-22 was absent in TME during initiation and hyperplasia stages of breast cancer. It was expressed during early carcinoma and significantly increased as tumor progressed to malignant stage. In human samples, IL-22 was poorly expressed in high and low grade ductal carcinoma in situ. However, it was significantly higher in invasive or metastatic carcinoma compared to ductal carcinoma in situ. Histological examinations revealed an inhibition in the malignant transformation of epithelial cells during invasion stage in IL-22-/- tumors. No difference was observed in initiation and hyperplasia stages of cancer between IL-22-/- and control mice. Ex vivo treatment of IL-22 increased the migration and invasion, but not the proliferation, of purified epithelial cancer cells. RNAseq analysis of premalignant stage epithelial cells revealed down regulation in genes associated with EMT (Epithelial to Mesenchymal Transition) pathway in IL-22-/- mice. These results show that, in breast cancer, IL-22 is not essential for cell proliferation but it is necessary for malignant transformation of cancer cells which is the critical stage for metastasis. Inhibition of IL-22 can hinder cancer cell malignancy and therefore, it can be an effective therapeutic target to control breast cancer metastasis.
Citation Format: Gajendra K. Katara, Arpita Kulshrestha, Sylvia Schneiderman, Safaa Ibrahim, Mahmood Bilal, Valerie E. Riehl, Kenneth D. Beaman. IL-22 is specifically required for malignancy in breast cancer: A potential target to control cancer metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4600.
Abstract 4608: Colchicine binding site agents as potent tubulin inhibitors suppressing triple negative breast cancer
Authors: Deng Shanshan , Chen Hao , Krutilina Raisa , Albadari Najah G. , Seagroves Tiffany N. , Miller Duane D. , Li Wei 
Published: August 2019

Abstract
Triple-negative breast cancer (TNBC) cases account for about 15% of all breast cancers in the United States and have poorer overall prognosis relative to other molecular subtypes, partially due to the rapid development of drug resistance to chemotherapies and the increased risk of visceral metastasis. One of the standard treatment regimens for TNBC is the use of a taxane-based chemotherapy, such as paclitaxel, which stabilizes microtubules. However, drug resistance and neurotoxicities often limit the clinical efficacy of taxanes. Therefore, there are continuous needs to develop more effective therapies that could overcome resistance to taxanes. In this study, a novel series of structurally related pyridine analogs based on our previously reported lead compound ABI-274, was designed and synthesized to identify a molecule with improved antiproliferative potency. Most of these pyridine compounds exhibited potent cytotoxicity when tested in a panel of melanoma and breast cancer cell lines, with IC50 values in the low nanomolar range. Among them, CH-II-77 is the most potent compound with an IC50 value of 1−3 nM against these cancer cell lines, including paclitaxel-resistant sublines. The high-resolution X-ray crystal structure of CH-II-77 in complex with tubulin protein confirmed its direct binding to the colchicine-binding site. It strongly induced apoptosis and produced G2/M phase cell cycle arrest in TNBC cells in a dose-dependent manner in vitro. In vivo, CH-II-77 inhibited tumor growth in A375 melanoma xenografts and MDA-MB-231 TNBC xenografts in a dose-dependent manner. CH-II-77 was able to induce tumor necrosis and apoptosis in vivo. Collectively, these studies strongly suggest that CH-II-77 is a potent inhibitor of the growth of TNBC in vitro and in vivo. Thus, CH-II-77 and optimization of this analog are promising new generation of tubulin inhibitors for the treatment of TNBC and other types of cancers where tubulin inhibitors are currently being used clinically.
Citation Format: Shanshan Deng, Hao Chen, Raisa Krutilina, Najah G. Albadari, Tiffany N. Seagroves, Duane D. Miller, Wei Li. Colchicine binding site agents as potent tubulin inhibitors suppressing triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4608.
Abstract 4617: In vivo efficacy focused data collection and gaps for preclinical anticancer drug evaluation
Authors: Chen Taiping , Sun Xiaoqin , Li Tingting 
Published: August 2019

Abstract
Even though most anticancer drugs have been initially screened, investigated, and evaluated with variety of in vitro platforms, gaps between preclinical nominated candidate and clinical acceptable approval of final drug remain a big challenge for biotech companies all over the world. It is a highly demanding task to establish various animal models which can closely mimic human tumorigenesis in preclinical drug evaluation. Here we summarize several in vivo efficacy models to discuss on various applications in the data collection and interpretation. Currently available models include traditional cancer cell derived xenograft (CDX), patient derived xenograft (PDX), immune component murine tumor models (syngeneic and human gene knock-in), and orthotopic tumor models. Based on different drug mechanisms appropriate models will be initially selected with certain rationale. In order to understand the in vivo mechanisms of action (MOA) and drug target relevance, biomarker profiling and pharmacodynamic changes will be investigated with IHC, and/or FACS analysis particularly when the test articles display clear efficacious responses. Some representative data will be presented to demonstrate that in vivo efficacy will be the key endpoint for further analysis and clinical trial support. Small and large molecules of targeted drugs, antibody drug conjugate (ADC), immune checkpoint therapeutics will be included in the discussion. In sum, the approaches of in vivo data collection here are feasible to support many drug candidates to be evaluated to fill the gaps in the clinical drug development.
Citation Format: Taiping Chen, Xiaoqin Sun, Tingting Li. In vivo efficacy focused data collection and gaps for preclinical anticancer drug evaluation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4617.
Abstract 4622: The YUMMER.G mouse melanoma model recapitulates the heterogeneous response to immune checkpoint blockade based on patient sex
Authors: Ramseier Julie Y. , Charos Alexandra , Park Koonam , Damsky William , Bosenberg Marcus W. 
Published: August 2019

Abstract
Existing murine melanoma models, such as syngeneic transplantation of the B16 melanoma cell line, are aggressive, but poorly immunogenic, and as a result, studying the response to immunotherapy in these models has been challenging. Furthermore, in humans, a heterogeneous response to immune checkpoint inhibitor therapy has been observed between male and female melanoma patients, yet no immunogenic murine cancer model exists to study this sex-related dimorphism. To address these challenges, we created the YUMMER.G model, a melanoma cell line driven by human-relevant Braf activation and loss of Pten and Cdkn2a. YUMMER.G is related to the previously described YUMMER1.7 model; however important differences include: diploid state, female genotype, and Mc1re/e (pheomelanin producing) background. YUMMER.G was created by treatment with UV-light, resulting in a neoantigen rich subclone. Subcutaneous injection of 2 million YUMMER.G cells into C57BL/6J mice resulted in melanoma formation in both male and female mice. Treatment of established tumors with anti-CTLA-4 resulted in a comparable response between male and female mice, with complete, durable tumor regression in 100% of female mice and 88% of male mice. However, when established YUMMER.G tumors were treated with anti-PD-1, 63% of female mice, but only 13% of male mice exhibited complete tumor regression (p = 0.0330). These findings demonstrate the important role of host sex in the response to immunotherapy, and they parallel the sex-related differences in checkpoint inhibitor efficacy that have been observed in human patients. In summary, the YUMMER.G model is a human-relevant, immunogenic mouse melanoma model that will serve as a valuable platform for further investigating the mechanisms that mediate the sex-related dimorphism in anti-tumor immunity and response to immunotherapy.
Citation Format: Julie Y. Ramseier, Alexandra Charos, Koonam Park, William Damsky, Marcus W. Bosenberg. The YUMMER.G mouse melanoma model recapitulates the heterogeneous response to immune checkpoint blockade based on patient sex [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4622.
Abstract 4629: FOXA2 controls tumor-associated inflammation inKRAS-mutant lung cancer
Authors: Tomoshige Koichi , Guo Minzhe , Fink-Baldauf Iris , Stuart William , Maeda Yutaka 
Published: August 2019

Abstract
Background: Although the role of the transcription factor FOXA2 in lung cancer has been investigated using mouse and human lung cancer cell lines, to our knowledge, the role of FOXA2 in autochthonous lung tumors in GEMM (Genetically Engineered Mouse Model) has not been determined.
Methods: In order to determine the role of FOXA2 in autochthonous lung tumor cells, we deleted FOXA2 in lung epithelia of Kras-mutant lung cancer model mice (Scgb1a1-Cre;[tetO]-Kras4bG12D;Foxa2flox/flox, a GEMM) and assessed survival and lung histology of the GEMM.
Results: Deletion of FOXA2 in autochthonous Kras-mutant lung tumor cells significantly extended the survival of Kras-mutant lung cancer model mice (median survival from 8 weeks to 23 weeks; n&gt;14 for each group). Histological analysis indicated that FOXA2 was required for the growth of lung tumor cells and the recruitment of tumor-associated macrophages.
Conclusion: FOXA2 promotes primary KRAS-mutant lung tumors in part by controlling tumor-associated inflammation.
Citation Format: Koichi Tomoshige, Minzhe Guo, Iris Fink-Baldauf, William Stuart, Yutaka Maeda. FOXA2 controls tumor-associated inflammation inKRAS-mutant lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4629.