bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1507: Transcriptional profiles of CD14+ cells in situ in melanoma tumors reveal plasticity and localization dependent function
Authors: Martinek Jan , Kim Kyung In , Wu Te-Chia , Wang Victor , Brookes Hannah M. , Sun Lili , Gulati Ananya , George Joshy , Henrich Philipp , Marches Florentina , Rongvaux Anthony , Chiorazzi Michael , Chuang Jeff , Robson Paul , Flavell Richard , Banchereau Jacques , Palucka Karolina 
Published: August 2019

Abstract
Mechanisms contributing to immunotherapy resistance in patients are the object of intense studies. Myeloid cells play a major role in tumors and include cells with different functions that can be grossly summarized as: (1) Antigen capture for presentation (dendritic cells, DCs) or for degradation (macrophages); (2) Tissue repair (macrophages) and (3) Effector function (mast cells, monocytes, granulocytes). However, the functional states of myeloid cells in human tumors are not completely understood. To study intact tumor microenvironments we have established a comprehensive approach for cellular and molecular analysis. Modular analysis of bulk RNAseq data of whole melanoma tissue sections stratified patient samples based on lymphocytic infiltrate but revealed inflammation and myeloid modules spread across samples. Polychromatic immunofluorescence and histocytometry showed that CD14+ cells represent the majority of the total tumor immune infiltrate. Furthermore, the majority of T cells present in melanoma tissue are in direct contact with CD14+ cells rather than melanoma cells. The distribution of CD14+ cells shows two distinct patterns: CD14+ cells within cancer nests (intratumoral) which are in close proximity to melanoma cells and are loaded with melanoma protein; CD14+ cells in the tissue surrounding cancer nests (stromal) which do not contain melanoma protein cargo and are organized in dense infiltrates. Using customized immunofluorescence-guided laser capture micro-dissection, we harvested CD14+ cells based on their tissue location and melanoma protein load for downstream analysis. We find that unsupervised clustering of transcriptomes groups cells by their tissue localization, i.e., intratumoral vs. stromal. Computational analysis, revealed distinct and replicable gene signatures associated with different pathways, in intratumoral and stromal CD14+ cells. Thus, the transcriptome differentiates the functional status of CD14+ cells related to their localization within tumor.
Citation Format: Jan Martinek, Kyung In Kim, Te-Chia Wu, Victor Wang, Hannah M. Brookes, Lili Sun, Ananya Gulati, Joshy George, Philipp Henrich, Florentina Marches, Anthony Rongvaux, Michael Chiorazzi, Jeff Chuang, Paul Robson, Richard Flavell, Jacques Banchereau, Karolina Palucka. Transcriptional profiles of CD14+ cells in situ in melanoma tumors reveal plasticity and localization dependent 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 1507.
Abstract 1517: Targeting M-MDSC intrinsic enhancer reprogramming enhances the efficacy of immune checkpoint therapy in hepatocellular carcinoma
Authors: Liu Man , Zhou Jingying , Cheng Alfred Sze Lok 
Published: August 2019

Abstract
Fibrous liver promotes an immunosuppressive environment to facilitate hepatocellular carcinoma (HCC) initiation. However, the underlying mechanisms of liver fibrosis-elicited immune evasion are poorly elucidated. Myeloid derived suppressor cells (MDSCs) play a key role in immunosuppression, leading to low responsiveness of immune checkpoint blockade (ICB). Emerging evidence highlights the pivotal role of enhancer remodeling in cell identity establishment and tumor immunity. Therefore, we aimed to determine whether enhancer remodeling participates in MDSC generation and aggressive HCC development in fibrous liver, and further explore the potential of enhancer inhibition in targeting MDSCs and improving efficacy of ICB in fibrotic HCC treatment.
By a mouse hepatoma cell Hepa1-6 orthotopic fibrotic HCC mouse model, we found that monocytic MDSC (M-MDSC) subset was also dramatically expanded in murine fibrous liver and positively correlated with increased hepatic tumorigenicity. Hepatic stellate cell (HSC), as key profibrogenic stromal cell, stimulated immunosuppressive M-MDSC generation from human peripheral blood mononuclear cells (PBMCs). Mechanistically, activated HSCs initiated p38 MAPK-mediated enhancer remodeling and triggered monocyte-to-M-MDSC identity shifting. Enhancer inhibition by a clinically-trialed drug iBET-762 disrupted HSC-M-MDSC crosstalk and abrogated M-MDSC generation and immunosuppressive functions. Notably, combination of iBET-762 with anti-PD-L1 antibody significantly induced tumor-infiltrating T lymphocytes, leading to tumor eradication and prolonged host survival in fibrosis-associated HCC model. As we also showed profound suppression of HCC patient-derived M-MDSCs by enhancer inhibition, our results delineate an enhancer deregulation mechanism for M-MDSC generation in fibrous liver environment, highlighting a promising therapeutic strategy of combined enhancer and immune-checkpoint targeting for desmoplastic tumors.
This project is supported by Collaborative Research Fund C4017-14G and the Focused Innovations Scheme 1907309.
Citation Format: Man Liu, Jingying Zhou, Alfred Sze Lok Cheng. Targeting M-MDSC intrinsic enhancer reprogramming enhances the efficacy of immune checkpoint therapy in hepatocellular carcinoma [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 1517.
Abstract 1526: Colitis promotes intrahepatic cholangiocarcinoma via gut microbiome dependent, CXCL1/CXCR2 mediated MDSC accumulation
Authors: Zhang Qianfei , Ma Chi , Rosato Umberto , Heinrich Bernd , Fu Qiong , Laurence Diggs , Greten Tim 
Published: August 2019

Abstract
Inflammatory bowel disease (IBD) is a known risk factor for cholangiocarcinoma. Gut microbiome dysregulation is closely associate with IBD, however, its role in IBD-promoted cholangiocarcinoma is unknown. Here, we established a preclinical mouse model recapitulating the tumor-promoting effect of IBD on cholangiocarcinoma. Increased translocation of gut bacteria to liver is observed in IBD. Oral antibiotic-mediated bacterial depleting shows that neomycin- but not vancomycin-sensitive bacteria mediate the IBD-accelerated tumor progression without affecting IBD disease status. Gut microbiome regulates anti-tumor immunity. A robust increase of hepatic CXCR2+ granulocytic myeloid-derived suppressor cells (G-MDSC) was observed, which is caused by IBD and can be blocked by oral neomycin treatment, but not dependent on tumor-bearing condition, gender or mouse strain. Depleting the increased hepatic G-MDSC abolished the IBD-enhanced tumor progression. The liver accumulation of CXCR2+ G-MDSC was regulated by CXCL1 expression of hepatocytes, which was controlled by gut microbiome-mediated LPS/TLR4 axis. The increase of liver granulocytes can also be found in patients with active IBD. Our study provides novel knowledge that bacterial dysregulation in IBD fosters a tumor-promoting environment in liver and contributes to cholangiocarcinoma disease progression.
Citation Format: Qianfei Zhang, Chi Ma, Umberto Rosato, Bernd Heinrich, Qiong Fu, Laurence Diggs, Tim Greten. Colitis promotes intrahepatic cholangiocarcinoma via gut microbiome dependent, CXCL1/CXCR2 mediated MDSC accumulation [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 1526.
Abstract 1534: MEDI5083, a novel CD40L-Fc fusion protein, activates the CD40 pathway on antigen presenting cells and promotes a robust anti-tumor immune response in a B16F10 murine tumor model
Authors: Turman Sean , McGlinchey Kelly , Wang YaYa , Malhotra Deepali , Herbst Ronald , Wang Yue 
Published: August 2019

Abstract
Targeting CD40 with its natural ligand (CD40L) enhances the immune-stimulatory functions of dendritic cells, B cells, monocytes and macrophages, resulting in T cell priming, expansion and differentiation. Thus, activation of the CD40 pathway is an attractive strategy to boost anti-tumor immune responses. MEDI5083 is a novel fusion protein consisting of a hexameric recombinant human CD40L structure covalently linked to human IgG4p Fc. In this study, we present the functional characterization of MEDI5083. MEDI5083 specifically bound to human CD40 and triggered surface CD40 internalization. As a result, MEDI5083 exerted robust CD40 agonist activities as measured by NF-κb activation in Ramos and THP1 cell lines. In assays using primary human B cells and myeloid cells, MEDI5083 potently upregulated co-stimulation molecules including MHCII, CD80 and CD86, and induced secretion of pro-inflammatory cytokines, such as TNFα and IL6. To examine the anti-tumor activity in mice, we constructed a murine surrogate of MEDI5083 (mCD40L-Fc) which has similar physical and target binding properties to those of MEDI5083. In the B16F10 syngeneic mouse model, repeated dosing of mCD40L-Fc significantly decreased tumor volume and/or delayed tumor growth, compared with isotype control dosed animals. Combination treatment of mCD40L-Fc with anti-PD-L1 and/or anti-CTLA-4 further enhanced the anti-tumor immune response. Moreover, treatment with mCD40L-Fc alone or in combination with anti-PD-L1 or anti-CTLA-4 induced elevated levels of TH1 cytokines IFNγ and IL12 in serum, and increased numbers of intratumoral CD8+ T cells, compared with isotype control treated animals. Thus, mCD40L-Fc elicits robust immune activation and significant anti-tumor activity against B16F10 tumors, which have low responsiveness to checkpoint inhibitors. The insights obtained from the preclinical studies support the development of MEDI5083, which is currently in clinical development for a broad spectrum of malignancies.
Citation Format: Sean Turman, Kelly McGlinchey, YaYa Wang, Deepali Malhotra, Ronald Herbst, Yue Wang. MEDI5083, a novel CD40L-Fc fusion protein, activates the CD40 pathway on antigen presenting cells and promotes a robust anti-tumor immune response in a B16F10 murine tumor model [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 1534.
Abstract 154: Inhibition of pancreatic cancer Panc-1 cell migration by omeprazole is dependent on aryl hydrocarbon receptor activation of JNK
Authors: Jin Unho , Karki Keshav , Safe Stephen 
Published: August 2019

Abstract
Aryl hydrocarbon receptor (AhR)-active pharmaceuticals were screened as inhibitors of pancreatic cancer cell invasion and identified two compounds, omeprazole, that inhibited invasion. Inhibition of highly invasive Panc1 cell invasion by omeprazole involves an AhR-dependent non-genomic pathway, and omeprazolemediated inhibition of Panc1 cell invasion was dependent on Jun-N-terminal kinase and mitogen-activated kinase kinase 7 (MKK7). Results of RNAseq studies indicate that omeprazole induced an AhR-dependent downregulation of several pro-invasion factors including activated leukocyte cell adhesion molecule, long chain fatty acid CoA-synthase, stathmin 3 and neuropillin 2, and the specific functions of these genes are currently being investigated.
Citation Format: Unho Jin, Keshav Karki, Stephen Safe. Inhibition of pancreatic cancer Panc-1 cell migration by omeprazole is dependent on aryl hydrocarbon receptor activation of JNK [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 154.
Abstract 1554: Uncoupling tumor-cell cytotoxicity from cytokine release with novel T-cell engaging bispecific antibodies
Authors: Lorentsen Kyle , Sankaran Preethi , Trinklein Nathan D. , Pham Duy , Schellenberger Ute , Buelow Ben , Boudreau Andrew , Choudhry Priya , Clarke Starlynn C. , Dang Kevin , Harris Katherine E. , Iyer Suhasini , Jorgensen Brett , Pratap Payal , Rangaswamy Udaya S. , Ugamraj Harshad S. , Vafa Omid , Wiita Arun P. , Schooten Wim van , Buelow Roland , Aldred Shelley Force 
Published: August 2019

Abstract
T-cell recruiting bispecific antibody (T-BsAb) treatment is an emerging cancer immunotherapy notable for its highly-specific tumor killing activity in humans. However, the success of T-BsAbs in the clinic has been limited due to cytokine-release related toxicities. In order for this technology to reach its potential, the next generation of T-BsAbs must avoid this unintended toxicity by uncoupling cytokine-release from tumor-cell killing. To this end, we used a sequence-based discovery method on CD3-immunized OmniFlic rats, which express human fixed light-chain antibodies, to identify several novel anti-CD3 antibodies. These antibodies bind to multiple CD3 epitopes, each with varying affinities and degrees of T-cell activation. Furthermore, when placed in the context of a T-BsAb, these novel anti-CD3 antibodies achieve similar levels of T-cell mediated tumor-specific lysis, but with a thousand-fold range in potency. Among these antibodies, we identified one lead with particularly favorable properties, in that it stimulates very low levels of cytokine production without sacrificing its potent antigen-specific tumor lysis in vitro, in mouse xenograft assays, as well as ex vivo patient sample studies. This unique behavior gives our novel anti-CD3 antibody the potential to widen the therapeutic window when treating patients and ultimately usher in the next generation of T-BsAbs.
Citation Format: Kyle Lorentsen, Preethi Sankaran, Nathan D. Trinklein, Duy Pham, Ute Schellenberger, Ben Buelow, Andrew Boudreau, Priya Choudhry, Starlynn C. Clarke, Kevin Dang, Katherine E. Harris, Suhasini Iyer, Brett Jorgensen, Payal Pratap, Udaya S. Rangaswamy, Harshad S. Ugamraj, Omid Vafa, Arun P. Wiita, Wim van Schooten, Roland Buelow, Shelley Force Aldred. Uncoupling tumor-cell cytotoxicity from cytokine release with novel T-cell engaging bispecific antibodies [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 1554.
Abstract 1559: TLR7/8 immune-stimulating antibody conjugates elicit robust myeloid activation leading to enhanced effector function and anti-tumor immunity in pre-clinical models
Authors: Ackerman Shelley E. , Gonzalez Joseph C. , Gregorio Josh D. , Paik Jason C. , Hartmann Felix J. , Kenkel Justin A. , Lee Arthur , Luo Angela , Pearson Cecelia I. , Nguyen Murray L. , Ackerman Benjamin , Sheu Lauren Y. , Laura Richard P. , Chapin Steven J. , Safina Brian S. , Bendall Sean C. , Dornan David , Engleman Edgar G. , Alonso Michael N. 
Published: August 2019

Abstract
Deficient anti-tumor immunity often results from an immunosuppressive tumor microenvironment (TME) that renders antigen presenting cells (APCs) unable to effectively stimulate T cells. Recent studies indicate that local delivery of immunostimulatory adjuvants can activate tumor resident APCs, driving uptake, processing and presentation of tumor neoantigens to T cells that mediate anti-tumor immunity. To overcome challenges associated with intratumoral delivery of such adjuvants, we developed a novel class of TLR immune-stimulating antibody conjugates (TAC) that comprise a TLR7/8 agonist conjugated to tumor-targeting monoclonal antibodies. In vitro co-cultures with human cancer cell lines and leukocytes revealed that TACs potently activate primary APCs, leading to increased co-stimulatory molecule expression (e.g. CD40, CD86) and secretion of pro-inflammatory cytokines (e.g. TNFα). The TACs also enhanced antibody-mediated effector functions such as ADCC and ADCP. Surprisingly, these constructs also induced dendritic cell (DC) differentiation from monocytes, as measured by changes in cellular morphology and DC surface markers (e.g. CD14 downregulation). CyTOF-based analysis of intracellular signaling in human leukocytes revealed a unique signaling signature of the conjugate compared to a mixture of its components, suggesting a novel biological mechanism by which the conjugate stimulates APCs. Finally, we demonstrated in vivo efficacy in syngeneic tumor models in which TAC treatment led to tumor clearance and development of immunologic memory. These results provide a strong rationale for this technology as a platform for cancer immunotherapy.
Citation Format: Shelley E. Ackerman, Joseph C. Gonzalez, Josh D. Gregorio, Jason C. Paik, Felix J. Hartmann, Justin A. Kenkel, Arthur Lee, Angela Luo, Cecelia I. Pearson, Murray L. Nguyen, Benjamin Ackerman, Lauren Y. Sheu, Richard P. Laura, Steven J. Chapin, Brian S. Safina, Sean C. Bendall, David Dornan, Edgar G. Engleman, Michael N. Alonso. TLR7/8 immune-stimulating antibody conjugates elicit robust myeloid activation leading to enhanced effector function and anti-tumor immunity in pre-clinical models [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 1559.
Abstract 1577: Telomerase reverse transcriptase (TERT) promoter mutations in cancers derived from multiple organ sites among Middle Eastern population
Authors: Bu Rong , Siraj Abdul K. , Iqbal Kaleem , Parvathareddy Sandeep , Diaz Mark , Rala Dionne , Victoria Ingrid G. , Al-Obaisi Khadija , Al-Haqawi Wael , Siraj Nabil , Benito Allianah , Al-Kuraya Khawla S. 
Published: August 2019

Abstract
Activation of telomerase induced by telomerase reverse transcriptase (TERT) promoter mutations has been implicated in human carcinogenesis. The two mutations termed C228T and C250T in TERT promoter region have been reported in various human tumor entities with different frequencies in Western populations. However, the contribution of these mutations to cancer progression in the Middle Eastern region remains poorly understood. In this study we investigated the frequency of TERT promoter mutations and TERT protein expression with their association to clinicopathological characteristics in 2113 samples from 13 different types of cancers. The TERT promoter mutations were most frequently present in bladder cancers (68.6%), followed by anaplastic thyroid cancers (50%), Hurthle cell carcinomas (40%), central nervous system (CNS) tumors (28.7%) and follicular thyroid cancers (19%). The low frequency of these mutations was found in medullary thyroid cancers (10%), prostate cancers (9.3%), endometrial carcinomas (3.7%), rhabdomyosarcomas (1.4%), colorectal cancers (CRC) (1%), epithelial ovarian carcinomas (EOC) (0.7%) and breast cancers (0.7%). No mutations were observed in gastric cancers, lung cancers, diffuse large B-cell lymphomas (DLBCL) and acute lymphoblastic leukemias (ALL). In CNS tumors the TERT promoter mutations were significantly associated with older age (p&lt;0.0001), histological subtype (p&lt;0.0001), high grade (p&lt;0.0001) and poor 5 years overall survival (p&lt;0.0001). In gliomas, TERT promoter mutations were more frequently present in cases with old age (p=0.003), high grade (p&lt;0.0001) and poor 5 years overall survival (p&lt;0.0001). Furthermore it was also revealed that co-occurrence of TERT promoter mutations and IDH1 wildtype predicted worst survival (p=0.0001) in gliomas. Our results demonstrate that mutations in TERT promoter is a frequently occurring event in several types of cancers and may be utilized for prognostic prediction in CNS tumors from Middle Eastern Region.
Citation Format: Rong Bu, Abdul K. Siraj, Kaleem Iqbal, Sandeep Parvathareddy, Mark Diaz, Dionne Rala, Ingrid G. Victoria, Khadija Al-Obaisi, Wael Al-Haqawi, Nabil Siraj, Allianah Benito, Khawla S. Al-Kuraya. Telomerase reverse transcriptase (TERT) promoter mutations in cancers derived from multiple organ sites among Middle Eastern population [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 1577.
Abstract 161: TRIM21 suppresses invasion of breast cancer cells
Authors: Hu Xin , Jin Yue , Zhang Yu , Li Boyuan , Wan Youzhong 
Published: August 2019

Abstract
Trim21 is an E3 ligase that is involved in the regulation of metastasis. High-level expression of TRIM21 is associated with good prognosis of breast cancer. After transplantation in immunodeficient mice, TRIM21-depleted MCF7 cells form tumors that show evident local invasion, i.e., extensive infiltration of single tumor cells into nearby muscle fibers. Knockdown of TRIM21 increases the migration and invasion of MCF7 and T47D cells by altering the expression of genes that regulate epithelial to mesenchymal transition(EMT). TRIM21 interacts with Snail, a master regulator of EMT, and the B-Box domain of TRIM21 is essential for the interaction between TRIM21 and Snail. Overexpression of TRIM21 leads to increased ubiquitination and subsequent proteosomal degradation of Snail, while depletion of TRIM21 decreases the ubiquitination and degradation of Snail. Most Importantly, knockdown of Snail suppresses the increased migration and invasion of MCF7 and T47D cells caused by TRIM21 knockdown. Collectively, our study demonstrates that TRIM21 modulates EMT by mediating the stability of Snail in breast cancer cells.
Citation Format: Xin Hu, Yue Jin, Yu Zhang, Boyuan Li, Youzhong Wan. TRIM21 suppresses invasion of breast cancer cells [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 161.