bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4968: Blockade of p38 kinase impedes the mobilization of myeloid populations that promote breast cancer metastasis
Authors: Zonneville Justin , Colligan Sean , Wallace Paul , Abrams Scott I. , Bakin Andrei V. 
Published: September 2020

Abstract
Patients with metastatic breast cancer (MBC) have limited therapeutic options and novel treatments are critically needed. Prior studies demonstrated that the p38 kinase (p38) promotes MBC, while the mechanisms remained unknown. Here, we provide evidence for a novel mechanism by which p38 promotes metastasis. Using triple-negative breast cancer models, we showed that a selective inhibitor of p38 (p38i) significantly reduced tumor growth, angiogenesis, and lung metastasis. Importantly, p38i decreased the accumulation of myeloid populations, namely myeloid-derived suppressor cells (MDSCs) and CD163+ tumor-associated macrophages (TAMs). p38 controlled the expression of tumor-derived chemokines/cytokines that facilitated the recruitment of pro-tumor myeloid populations. Depletion of MDSCs was accompanied by reduced TAM infiltration and phenocopied the anti-metastatic effects of p38i. Reciprocally, p38i increased tumor infiltration by cytotoxic CD8+ T cells. Metadata showed that a reduced CD163+/CD8+ expression ratio correlates with metastasis-free survival in breast cancer, suggesting that targeting p38 may improve clinical outcomes. This study highlights a novel p38-driven mechanism as a therapeutic target in MBC.
Citation Format: Justin Zonneville, Sean Colligan, Paul Wallace, Scott I. Abrams, Andrei V. Bakin. Blockade of p38 kinase impedes the mobilization of myeloid populations that promote breast cancer metastasis [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4968.
Abstract 4974: Q702, selective Axl/Mer/CSF1R triple kinase inhibitor enhance the activity of immune checkpoint inhibitor by alteration of immunosuppressive tumor microenvironment
Authors: Yang Yeong-In , Kang Hwankyu , Park Dongsik , Jeon Yeejin , Kim Jeongjun , Choi Baejung , Kim Jaeseung , Nam Kiyean 
Published: September 2020

Abstract
Central to the Immune Checkpoint Inhibitors (ICI) mechanism is the activation and infiltration of the cytotoxic CD8+ T cells following tumor-antigen recognition. However, the effector functions of the CD8+ T cells can be highly compromised by immunosuppressive tumor microenvironment (TME). There is the growing appreciation of the potential contributions of innate immune modulation to antitumor immunity which suggests the need for the novel strategies to elicit a more efficient/robust immune response against malignant cells. Axl/Mer/CSF1R play vital roles in the immunosuppressive TME by increasing regulatory T cell, M2 macrophage, myeloid-derived suppression cell (MDSC) and suppressing antigen presentation. Previously, we have reported a novel selective Axl/Mer/CSF1R kinase inhibitor, Q702 and demonstrated tumor regression by alteration of the immunosuppressive TME. We present the anti-tumor efficacy and immune mechanism of Q702 in combination with anti-PD-1 in the various syngeneic models. The combination of Q702 and anti-PD-1 demonstrated tumor regression through enhanced tumor infiltration of effector immune cells, altered cytokine expression promoting promoted tumor specific antigen presentation and unregulated PD-L1 expression on tumor cells. Additionally, the Q702 alone induced tumor regression in the anti-PD-1 non-responding syngeneic models. These results suggest that the innate immune modulation in the TME by Q702 in combination with an ICI can be through synergistic mechanisms of action. In addition, the data suggests that Q702 could potentially broaden the patient population that benefits from ICI-based immunotherapy. Q702 is progressing through IND-enabling studies to support initiation of a Phase 1 oncology clinical study in early 2020.
Citation Format: Yeong-In Yang, Hwankyu Kang, Dongsik Park, Yeejin Jeon, Jeongjun Kim, Baejung Choi, Jaeseung Kim, Kiyean Nam. Q702, selective Axl/Mer/CSF1R triple kinase inhibitor enhance the activity of immune checkpoint inhibitor by alteration of immunosuppressive tumor microenvironment [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4974.
Abstract 4979: Prevalence of proliferating CD8+cells in normal lymphatic tissues, inflammation and cancer
Authors: Lennartz Maximilian , Abu-Hashem Raed , Blessin Niclas Christian , Mandelkow Tim , Bady Elena , Simon Ronald , Hube-Magg Claudia , Sauter Guido , Fraune Christoph , Möller Katharina , Clauditz Till S. , Luebke Andreas M. , Büscheck Franziska 
Published: September 2020

Abstract
Expansion of CD8+ cytotoxic T lymphocytes is a prerequisite for anti-cancer immune activity. In the era of immune checkpoint therapy, profound knowledge of the dynamics of CD8+ has regained considerable interest. However, systematically acquired data on CD8+ proliferation in large sets of normal and diseased tissues are sparse. Here, we applied multiplex fluorescence immunohistochemistry to conventional large sections and tissue microarrays in order to quantitate Ki67+CD8+ cells in &gt;20 different compartments of normal lymphoid tissues, 7 types of inflammatory diseases and 785 cancers. In most normal lymphoid tissues (tonsil, lymph node, thymus, Peyer's patches, spleen, colon, appendix) the percentage of Ki67+CD8+ cells typically did not exceed 3%. The percentage of Ki67+CD8+ cells was markedly higher (45%) in the immune-active cortex of the thymus, however. In inflammatory conditions (including Hashimoto thyroiditis, Lichen sclerosus of the penis, sarcoidosis, sialadenitis, IgG4 pancreatitis, Crohn's disease and eczema), the percentage of Ki67+CD8+ cells was much more variable and often sharply higher than in normal tissues. It ranged from 0.5% in one patient with sialadenitis to 19% in the intraepithelial compartment of Crohn's disease. In 765 colorectal cancers, the fraction of Ki67 positive CD8+ cytotoxic T cells ranged from 0 to 100% (mean: 20.6%). A high fraction of Ki67+CD8+ cells was significantly associated with microsatellite instability (p&lt;0.0001), low pT stage (p&lt;0.0001) and absence of nodal metastases (p=0.0005). In summary, our data show a variable increase of the fraction of proliferating CD8+ T cells in cancers and in inflammatory diseases as compared to healthy secondary lymphoid organs. The striking link with microsatellite instability and unfavorable tumor features suggest a potential clinical utility of assessing Ki67+CD8+ in colorectal cancer.
Citation Format: Maximilian Lennartz, Raed Abu-Hashem, Niclas Christian Blessin, Tim Mandelkow, Elena Bady, Ronald Simon, Claudia Hube-Magg, Guido Sauter, Christoph Fraune, Katharina Möller, Till S. Clauditz, Andreas M. Luebke, Franziska Büscheck. Prevalence of proliferating CD8+cells in normal lymphatic tissues, inflammation and cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4979.
Abstract 4985: PD-L1 and diacylglycerol kinase alpha (DGKA) expression in melanoma, nsclc and bladder cancers
Authors: Gonzalez Rachel M. , Qu Tianli , Hu Xiaomin , Ren Qi , Zhang Qiankun , Guo Zhaoying , Kim Young-Hwan , Wang Yiran , Liu Xuan , Fu Wei 
Published: September 2020

Abstract
Diacylglycerol kinase alpha (DGKA) functions as lipid kinase to phosphorylate the lipid diacylglycerol (DAG). DGKA has been characterized to negative regulate the Ras-MAPK pathway in T lymphocytes. A 2018 study using crispr knockouts of DGKA have shown the anti tumor activity of T-cells continue to increase in the presence of PD-L1 positive tumor cells. Little is known about the expression patterns of DGKA in human cancer. In our previous study, we explore the tumor micro environment with a number of immune cell markers such as CD3, CD8A, CD20, CD68, TIM3 and LAG3 with PD-L1 expression in melanoma, NSCLC, and bladder cancer and found a few unique signatures for these cancers. In this study, we evaluate expression pattern of DGKA in various cancers by immunohistochemistry to elucidate the signature profile of DGKA expression with PD-L1 and other markers in the PD-L1 tumor micro environment.
Citation Format: Rachel M. Gonzalez, Tianli Qu, Xiaomin Hu, Qi Ren, Qiankun Zhang, Zhaoying Guo, Young-Hwan Kim, Yiran Wang, Xuan Liu, Wei Fu. PD-L1 and diacylglycerol kinase alpha (DGKA) expression in melanoma, nsclc and bladder cancers [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4985.
Abstract 4989: Introduction of a robust workflow for the whole-side acquisition and co-registration of multiplex immunofluorescence tissue images for analysis of a 9-color, 8-marker immunophenotyping assay
Authors: Hellebust Anne E. , Teplitz Kyla , Patel Katir K. , Sharma Karan , Bares Amanda , Manesse Mael , Burton Mark , Phillips Bonnie , Downing Sean , Lillard Kate 
Published: September 2020

Abstract
Background: Profiling multiple cell types in tissue samples requires more markers than can be supported by conventional approaches to immunohistochemistry. InSituPlex® multiplex immunofluorescence (mIF) technology enables biomarker multiplexing in tissue samples with an automated workflow to support discovery of immune cell signatures in the tumor immune microenvironment (TiME). Here we have designed and tested an 8-plex immunophenotyping panel using the InSituPlex approach to detect and classify T cells, macrophages, and tumor cells in non-small cell lung cancer (NSCLC) and colorectal cancer (CRC) FFPE tissue.
Methods: An 8-plex UltiMapper™ immunofluorescence was developed to stain FFPE tissue, including colorectal cancer, human tonsil, and non-small cell lung cancer. Each sample was stained for the following 8 markers: CD3, CD4, CD8, CD68, FoxP3, PD-1, PD-L1, and pan-CK. Whole-slide imaging was performed in two imaging rounds on the RareCyte CyteFinder II HT slide scanner, and same-slide image alignment and phenotypic analysis was performed using the HALO Highplex FL module from Indica Labs.
Results: Co-registration of two 4-plex imaging rounds and fusing into a single image file allowed for the seamless cell phenotyping of markers across imaging rounds. The 8-plex assay and workflow is compatible across multiple tumor sample types. The samples were characterized based on binned expression and co-expression of biomarkers. The following major cell phenotypes were detected: PD-L1 checkpoint expression, T cells (CD3+), cytotoxic T cells (CD3+/CD8+), T-helper cells (CD3+/CD4+), regulatory T-cells (CD3+/CD4+/FoxP3+), exhausted T cells (CD3+/PD-1+), macrophages (CD68+), and tumor cells (pan-CK+).
Conclusions: The 8-plex assay workflow involving InSituPlex mIF, CyteFinder HT scanner, and HALO analysis supports the ability to measure biomarkers in situ in streamlined and scalable approach.
Citation Format: Anne E. Hellebust, Kyla Teplitz, Katir K. Patel, Karan Sharma, Amanda Bares, Mael Manesse, Mark Burton, Bonnie Phillips, Sean Downing, Kate Lillard. Introduction of a robust workflow for the whole-side acquisition and co-registration of multiplex immunofluorescence tissue images for analysis of a 9-color, 8-marker immunophenotyping assay [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4989.
Abstract 4992: In vitro exhausted T cell assay for immuno-oncology candidates
Authors: Osmani Amin , Lamy Juliette , Janss Thibaut , Giltaire Séverine , Pattijn Sofie , Schockaert Jana 
Published: September 2020

Abstract
The need to better understand the tumour microenvironment (TME) dictates the characterization of the cell types involved, the roles they play and how they respond to treatment. To develop better cancer immunotherapies, in vitro primary immune cell bioassays offer an early assessment of their effects on the various players of the TME. Here we describe the development of an exhausted T cell assay and demonstrate its potential in identifying candidates that can reverse exhaustion. Exhausted T cells were first discovered in LCMV virus infections where chronic stimulation due to remaining virus antigens leads to T cells that stop responding to stimulation and lose their functionality (cytokine secretion and cytotoxic activity). The same phenotype was afterwards found in the tumor microenvironment where a lot of T cells were found to be “anergic”. Reversing their loss of functionality as a therapeutic strategy has made the characterization of these exhausted T cells a priority. Their phenotype is currently defined by an increase in the expression of a specific set of cell surface markers such as PD-1, TIM-3 and LAG-3. As exhaustion builds, the expression of these marker increases while T cell functionality decreases. The loss of functionality is defined by a reduction in cytokine secretion, proliferation and cytotoxic activity in the presence of an antigen. To evaluate this phenotype in more depth, transcription factors can also be monitored. For example, BLIMP-1 and BATF, which play a role in PD-1 expression, are shown to increase following exhaustion. Using primary immune cells, in vitro bioassays were developed to better screen the potential effect of new therapeutics on exhausted T cells. Their ability to reverse the exhausted phenotype and facilitate the anti-tumour immune response can as a result be assessed early in the drug development process. These experiments help advance our understanding of the tumour microenvironment and optimize the therapeutic effects of new drugs, design better clinical trials and ultimately discover relevant biomarkers.
Citation Format: Amin Osmani, Juliette Lamy, Thibaut Janss, Séverine Giltaire, Sofie Pattijn, Jana Schockaert. In vitro exhausted T cell assay for immuno-oncology candidates [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4992.
Abstract 4998: Integrative analyses in pediatric osteosarcomas to understand the role of GD2 associated to activated mTor for macrophage targeting
Authors: Pierrevelcin Marina , Lelong-Rebel Isabelle , Fuchs Quentin , Dontenwill Monique , Entz-Werle Natacha 
Published: September 2020

Abstract
Osteosarcoma is the most common primary malignant bone tumor in children and young adults. Its immune environment was described as predominantly involving M2 macrophages or osteoclasts. Previous studies were observing ganglioside GD2 expression on the osteosarcoma cell surface. Even more and more publications are deciphering the role of hypoxic biomarkers and its metabolic cell impact. Nevertheless, no links were, for instance, described clearly between mTor-HIF1 pathway and the macrophages in osteosarcomas through GD2 targeting. The aim of the study was to understand the role of all those molecular partners in osteosarcoma models. Material and methods: A cohort of 35 patients was explored to determine the expression by immunohistochemistry, as well as semi-quantitative PCR of several hypoxic and macrophages' biomarkers. Additionally, in 2D and 3D in vitro osteosarcoma models, analyses using metabolomics, western blotting, immunofluorescent imaging and RNA sequencing were performed to understand functional interactions between patient-derived osteosarcoma cells and the M2 macrophages. Endly, drug screening studies were testing 3D models (integrating matrix and hypoxic microenvironment) to assess efficacy of combinations using dinutuximab, mTor and HIF inhibitors. Results: Osteosarcoma samples are highly expressing CD163 and CD68 macrophage markers, as well as activated mTORC1 and GD2. Hypoxic biomarkers, when overexpressed, were statistically linked to a worst patient outcome. For macrophages and GD2 markers, a low expression was mostly linked to metastatic disease or poor response to chemotherapy. Specific metabolomic changes through glutaminolysis were frequently present and associated to a transcriptomic signature combining metabolism changes and specific immune macrophage environment. The targeting by dinutuximab associated to hypoxia inhibition was having a clear effect on osteosarcoma cell proliferation decrease, when associated to macrophages in 3D models mimicking osteosarcoma tumors. Conclusion: Macrophage immune environment is a key component of pediatric osteosarcomas and can be targeted in association with hypoxia inhibitors in 3D models recreating the osteosarcoma immune environment and bone matrix.
Citation Format: Marina Pierrevelcin, Isabelle Lelong-Rebel, Quentin Fuchs, Monique Dontenwill, Natacha Entz-Werle. Integrative analyses in pediatric osteosarcomas to understand the role of GD2 associated to activated mTor for macrophage targeting [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4998.
Abstract 5027: The mu-opioid receptor antagonist methylnaltrexone can decrease tumorigenesis in head and neck squamous cell carcinoma
Authors: Gorur Aysegul , Patino Miguel , Shi Ted , Takahashi Hideaki , Myers Jeffrey N. , Cata Juan P. 
Published: September 2020

Abstract
Head and neck cancer (HNC) is the sixth leading cause of cancer in the world, and the third most common neoplasia in developing countries [1]. Patients with HNC may suffer significant pain, for which opioids are commonly given. However, recent reports suggest that opioids may promote cancer progression by action on the mu-opioid receptor (MOR) [2, 3]. The goal of this research was to test the hypothesis that the MOR antagonist methylnaltrexone (MTNX) can decrease tumorigenesis in HN squamous cell carcinoma (SCC). First, we confirmed via RNAseq and western blot analyses that FaDu cells (a HNSCC line) express MOR. Then, we performed cyclic adenosine monophosphate (cAMP) activation enzyme-linked immunosorbent assay to evaluate the activity of MOR after activation with [D-Ala2N-Me-Phe4, Gly5-ol]-enkephalin (DAMGO), a selective MOR agonist. Short term (1hr) treatment with DAMGO decreased cAMP levels, suggesting full activity of the receptor. We conducted similar cAMP activity assays using MNTX. Our dose-dependent (10nM-1µM) experiments revealed that 1hr exposure of cells to MTNX inhibited cAMP activity, but not after 48 hrs of treatment, consistent with an inverse or partial agonist effect at low doses. To assess the impact of our findings on FaDu cell behaviors, we conducted in vitro proliferation, colony formation, and migration assays. MTNX at different concentrations (0.1nM, 1nM, 10nM, 100nM and 1µM) inhibited FaDu cell proliferative and metastatic cell behaviors (p&lt;0.05). To translate our results to in vivo, we inoculated the tongue of athymic nude mice with FaDu cells (200,000 cells/30 mL). Starting the day of cell inoculation, we randomly treated the animals with MNTX (subcutaneously, 1µg/kg, 10 µg/kg, and 100µg/kg) versus placebo (saline only) for 17 consecutive days. In vivo experiments demonstrated that administration of MTNX at three different concentrations delayed tumor progression and reduced tumor growth and formation compared to placebo (p&lt;0.0001). Overall, our results suggest that MTNX inhibits tumorigenesis of HNSCC, possibly by acting on MOR.
1. Siegel, R.L. et al, Cancer statistics, 2018. CA Cancer J Clin, 2018. 68(1): p. 7-30.
2. Lennon, F.E., et al, The mu-opioid receptor in cancer progression: is there a direct effect? Anesthesiology, 2012. 116(4): p. 940-5.
3. Patino, M.A., et al., The impact of intraoperative opioid use on survival after oral cancer surgery. Oral Oncol, 2017. 74: p. 1-7.
Citation Format: Aysegul Gorur, Miguel Patino, Ted Shi, Hideaki Takahashi, Jeffrey N. Myers, Juan P. Cata. The mu-opioid receptor antagonist methylnaltrexone can decrease tumorigenesis in head and neck squamous cell carcinoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5027.
Abstract 5032: Attenuated Salmonella blocks cancer metastasis by activating NK cells in an IFN-γ-dependent manner
Authors: Lin Qiubin , Rong Li , Huang Jiandong 
Published: September 2020

Abstract
Introduction and objectives:
The recent remarkable clinical results of cancer immunotherapies, such as immune checkpoint blockade and chimeric antigen receptor T cells (CAR-T), has sparked a great deal of enthusiasm in manipulating the immune response in the fight against cancer. Bacterial cancer therapies represent an alternative approach to targeting solid tumours for evoking anti-tumour immune responses. As a facultative anaerobic pathogen that can penetrate and colonize solid tumours, Salmonella typhimurium gained lot of interest in the investigation of bacterial cancer therapies and can exert its intrinsic antitumor activity by directly inducing systemic immune responses. However, most bacterial cancer therapies, including salmonella-based cancer therapies, have mainly focused on the suppression of already established tumours rather than metastasis.
Metastasis accounts for 90% of cancer related deaths and blocking of metastatic cascade has critical clinical impact. However, the clinical drug development for cancer treatment, including cancer immunotherapies, is evaluated largely depending on their ability to cause tumour shrinkage and ignores the effect on metastasis as it has proven challenging to target. Therefore, there is an urgent need for novel therapeutic strategies and agents targeting metastasis.
Experimental procedures and outcomes
Using an attenuated Salmonella typhimurium strain YB1 engineered by our lab, we have found a potent suppressive effect of attenuated salmonella on cancer metastasis, regardless of cancer types and genetic background, by evoking strong anti-metastatic immune response. Further study showed that suppression of cancer metastasis by attenuated Salmonella only requires the innate immune response. Among the many induced cytokines, we identified IFN-γ as an indispensable factor for inhibiting cancer metastasis. Based on CyTOF (mass cytometry or cytometry by time of flight) analysis of the innate immune responses after Salmonella treatment and antibody-mediated cell depletion, we further demonstrated that NK cells are the major factor involved in Salmonella-provoked metastasis suppression. We found that IFN-γ was mainly produced by NK cells during early Salmonella infection, and in turn, IFN-γ promoted the accumulation, activation and cytotoxicity of NK cells. The IFN-γ-dependent NK cells directly eliminated newly accumulated cancer cells in the lung to block the cancer metastasis cascade in response to the Salmonella treatment.
Citation Format: Qiubin Lin, Li Rong, Jiandong Huang. Attenuated Salmonella blocks cancer metastasis by activating NK cells in an IFN-γ-dependent manner [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5032.