bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1497: Identification of discrepancy between CTLA4 expression and CTLA4 activation in gastric cancer
Authors: Yu Yingyan 
Published: August 2019

Abstract
Objective: Recently, immune checkpoints blockers showed higher anti-tumor activity for advanced gastric cancer (GC). The purpose of the study is to find out biomarkers related to anti-CTLA4 therapy.
Materials and Methods: Datasets of GEO, TCGA and GESA were extracted. Differential expression of CTLA4 between cancer tissues and normal mucosa, enrichment of WT (wild type) vs CTLA4_KO (knockout) upregulated gene set and clinical significance were analyzed. The expression of CTLA4,CD3 and granzyme A (GZMA) were validated on 30 cases of Chinese GC. MSI marker MLH1 and EBV marker EBER were examined on 30 cases of Chinese GC by immunohistochemistry and in situ hybridization.
Results: CTLA4 was up-regulated in GC tissue relative to normal mucosa in datasets of GSE27342 (fold change=1.586, P&lt;0.001) and GSE63089 (fold change=1.365, P&lt;0.001). Increased CTLA4 expression was positively related to CTLA4 activation. EBV-associated GC (EBVaGC) and microsatellite instability GC (MSIGC) disclosed higher CTLA4 levels than other GCs. Genomic stability GC (GSGC) also showed higher enrichment score of CTLA4 activation. CTLA4 activation resulted in shorter overall survival in GC. The expression level of CTLA4 was well correlated to GZMA (R=0.701, P&lt;0.001) and CD3 (R=0.750, P&lt;0.001).
Conclusions: GSGC was firstly identified as the potential GC subtypes responsive to anti-CTLA4 treatment.
Note: This abstract was not presented at the meeting.
Citation Format: Yingyan Yu. Identification of discrepancy between CTLA4 expression and CTLA4 activation in gastric 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 1497.
Abstract 150: Stromal cell plasticity and immune surveillance revealed by single-cell transcriptomics
Authors: Regan Claire , Hao Yuan , Preall Jonathan 
Published: August 2019

Abstract
Pancreatic ductal adenocarcinomas are typically characterized by a highly desmoplastic stroma, which is dense in collagen and other extracellular matrix components that limit access to the growing tumor by immune cells and targeted therapies. ECM components are mainly deposited by cancer-associated fibroblasts (CAFs), which are thought to arise primarily from pancreatic stellate cells and have been shown to polarize into at least two distinct subtypes within the tumor microenvironment in response to extracellular ligands. Recent studies have suggested potentially antagonistic roles for the different CAF subtypes in either promoting or restraining tumor growth. While depletion of the restrictive desmoplasia is likely to be a desirable therapeutic avenue, a complete understanding of phenotypic variation and interconversion between CAF populations will be essential for designing targeted therapies.
Using single-cell RNAseq, we have profiled the non-immune stromal cells of pancreatic ductal adenocarcinomas in the KPC mouse model, as well as from orthotopically transplanted organoid-derived pancreatic tumors. In addition to the canonically reported myofibroblastic and inflammatory CAF subtypes, we observe at least one additional distinct type-I collagen expressing fibroblastic cell type in the tumor microenvironment. The high degree of transcriptional divergence suggests that these CAFs may arise from distinct progenitors, whereas myo- and inflammatory-CAFs lie along a continuous pseudotemporal gradient marked by signatures of transcriptional programs driven by extracellular ligand signaling, including Wnt-family genes. Our single-cell transcriptomic results point toward pathway utilization that could be exploited for modulating PDAC desmoplasia and enabling targeted combination therapies.
Citation Format: Claire Regan, Yuan Hao, Jonathan Preall. Stromal cell plasticity and immune surveillance revealed by single-cell transcriptomics [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 150.
Abstract 1503: Effect of immune cell depletion on the responses to PD1 treatment in syngeneic models
Authors: Jin Ying , Shan Yongli , An Annie Xiaoyu , Li Henry Qixiang , Ouyang Davy Xuesong 
Published: August 2019

Abstract
Immunological checkpoint inhibitors, i.e., PD1 or PD-L1 antibodies, reverse cancer immunosuppression and promote antitumor immune responses in several cancer types. However, targeting PD-1/PD-L1 axis is only effective in ~20% of cancer patients, while some of the initial responders also develop resistance to the treatment. It is critical to fully understand which lineages of immune cells play major roles mediating PD1 responses in a given tumor microenvironment. While it’s well-known that PD1 antibody works through activating cytotoxic T cells, the contributions of other immune cell populations in PD1 treatment are not well defined. To understand how different lineages of immune cells impact PD1 efficacy, we removed various immune cell subpopulations in MC38 and Hepa 1-6 murine models when treated with PD1 antibody. In this study, mice inoculated with MC38 or Hepa1-6 tumors were treated with PD1 antibody or a combination of PD1 with depletion antibodies. The effectiveness of immune cell depletion was assessed by flow cytometry. CD4-, CD8- T cells, NK cells, MDSC and macrophages were depleted with anti-CD4 (GK1.5), anti-CD8 (2.43), anti-NK1.1 (PK136), anti-GR1 (RB6-8C5) antibodies and clodronate liposomes, respectively. As expected, depletion of CD8 T cells completely abrogated the antitumor effect of PD1 treatment, confirmed the crucial roles for CD8 T cells in tumor killing. Surprisingly, depletion of CD4 T cells and macrophages showed quite opposite effects in MC38 and Hepa1-6 lines - while significantly sensitizing MC38 tumors to PD1 treatment, PD1 efficacy is deteriorated in Hepa1-6. Depletion of NK cells enhanced the tumor inhibition effect in Hepa1-6 with 4 tumors showed complete or partial regression, without significant impact on MC38 tumors. Taken together, our studies have shown an unequivocal role of CD8 T cells in PD1 induced tumor growth inhibition. However, other lineages of immune cells may act differently upon PD1 blockade release, presumably depending on specific tumor microenvironment. Additional study is needed to differentiate the effects of Treg depletion vs. non-Treg CD4 T cell depletion.
Citation Format: Ying Jin, Yongli Shan, Annie Xiaoyu An, Henry Qixiang Li, Davy Xuesong Ouyang. Effect of immune cell depletion on the responses to PD1 treatment in syngeneic 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 1503.
Abstract 1508: Primary tumors induce neutrophil extracellular traps with targetable metastasis promoting effects
Authors: Rayes Roni F. , Mouhanna Jack G. , Nicolau Ioana , Vourtzoumis Phil , Wong Carson , Eustache Jules , Bourdeau France , Giannias Betty , Siblini Aya , Lee Emma , Sangwan Veena , Rousseau Simon , Quail Daniela , Walsh Logan , Bertos Nicholas , Cools-Lartigue Jonathan , Ferri Lorenzo E. , Spicer Jonathan D. 
Published: August 2019

Abstract
Targeting the dynamic tumor immune microenvironment can provide effective therapeutic strategies for cancer. Neutrophils (polymorphonuclear neutrophils, PMNs) are the predominant circulating leukocyte population in humans and are vital to fight infection. Despite mounting evidence that PMNs can promote tumor progression, depleting PMNs is not a viable therapeutic option. Neutrophil extracellular traps (NETs) are networks of extracellular neutrophil DNA fibers that are capable of trapping tumor cells and promoting their growth and their metastasis. Targeting NETs can therefore be a potentially successful therapeutic option to block the tumor promoting functions of PMNs. Here we demonstrate that circulating NET levels are elevated in esophageal, gastric and lung cancer patients compared to healthy controls. This increase correlates with disease stage and NET levels are independent predictors of advanced stage. Using pre-clinical murine models of lung and colon cancer, we observe elevated NET levels in tumor bearing mice compared to non-tumor bearing mice; these levels correlated with tumor size. NET levels significantly decrease following tumor resection or treatment with DNase1, a NET degrader, or neutrophil elastase inhibitor (NEi), a NET inhibitor. NET levels do not rise following tumor inoculation in peptidyl arginine deiminase-IV knock out (PAD4-/-) mice; PAD4 being an enzyme essential for citrullination of histones, a crucial step in NET release. Moreover, PMNs from tumor bearing mice are more primed for NETosis than PMNs from non-tumor bearing mice or NEi-treated or PAD4-/- tumor bearing mice. Finally, elevated in vivo hepatic adhesion and spontaneous liver and lung metastases are observed in tumor bearing mice compared to DNase1- or NEi-treated or PAD4-/- tumor bearing mice. Therefore, inhibiting NETs represents a promising strategy to impede metastatic dissemination in several types of cancer patients.
Citation Format: Roni F. Rayes, Jack G. Mouhanna, Ioana Nicolau, Phil Vourtzoumis, Carson Wong, Jules Eustache, France Bourdeau, Betty Giannias, Aya Siblini, Emma Lee, Veena Sangwan, Simon Rousseau, Daniela Quail, Logan Walsh, Nicholas Bertos, Jonathan Cools-Lartigue, Lorenzo E. Ferri, Jonathan D. Spicer. Primary tumors induce neutrophil extracellular traps with targetable metastasis promoting effects [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 1508.
Abstract 1510: Androgen regulated IL-8 expression in prostate cancer: Insights into tumor cell mediated immunosuppression
Authors: Bujanda Zoila A. Lopez , Haffner Michael C. , Chaimowitz Matthew G. , Chowdhury Nivedita , Hurley Paula J. , Christiano Angela M. , Drake Charles G. 
Published: August 2019

Abstract
Androgen deprivation therapy (ADT) results in castration-resistant prostate cancer (CRPC) in a significant fraction of patients. We have previously reported that the protein levels of interleukin-8 (IL-8) were inversely correlated with disease progression in men with biochemical recurrent prostate cancer treated with Lenalidomide. Recently, polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) were implicated as potential drivers of CRPC. Here we show that IL-8 expression is upregulated as a consequence of ADT and mediates the recruitment of PMN-MDSCs to the tumor microenvironment. We found that IL-8 expression is regulated by both an inflammatory stimulus (NF-kβ mediated) and loss of androgen receptor (AR) signaling following ADT. We confirmed direct binding of both the p65 subunit of NF-kβ and AR to the IL-8 promoter, and their respective effects on promoter activity. The suppressive activity of AR was further supported by a reduction in active transcription markers at the chromatin level surrounding the IL-8 promoter. Accordingly, intratumoral infiltration of PMN-MDSCs correlated with IL-8 expression, and was reduced in IL-8 knockouts. Taken together, these results suggest an innate inflammatory response, loss of AR suppressive activity, and subsequent chemokine upregulation as a potential mechanism that regulates the infiltration of PMN-MDSCs to the tumor microenvironment of CRPC after ADT. These findings open a window of opportunity for therapeutic interventions aiming to improve responses to checkpoint blockade in prostate cancer.
Citation Format: Zoila A. Lopez Bujanda, Michael C. Haffner, Matthew G. Chaimowitz, Nivedita Chowdhury, Paula J. Hurley, Angela M. Christiano, Charles G. Drake. Androgen regulated IL-8 expression in prostate cancer: Insights into tumor cell mediated immunosuppression [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 1510.
Abstract 1525: Kaiso influences immune signaling of breast cancer exosomes
Authors: Ahmed Md Shakir U. , Jenkins Brittany , Adu-Addai Benjamin , Karanam Balasubramanyam , Davis Melissa B. , Grizzle William E. , Wang Honghe , Yates Clayton C. 
Published: August 2019

Abstract
Introduction: Exosomes are communication vesicles between tumor cells and immune cells. However, the mechanism underlining this cell-cell communication is not well understanding, particularly in African American (AA) breast cancer patients. Kaiso, a bi-modal transcription factor is highly expressed in AA patients and high Kaiso expression correlates with aggressiveness and the disparity in survival outcomes compared to European American (EA) patients. However, the biological consequences of Kaiso in immune signaling of breast cancer exosomes has not been studied. Herein we demonstrate the biological role of Kaiso in immune signaling in breast cancer exosomes.
Methods: We utilized Nanostring immune profiling technology along with multiple in vitro and in vivo assays to study the role of Kaiso in breast cancer immune escape.
Results: Nanostring pan cancer immune profiling showed that EA breast cancer exosomes exhibited higher expression of TILs markers, T cell activation markers and CD8+T Cells markers compared to AA, while we observed an increase in the expression of anti-phagocytic molecule CD47 in breast cancer patient exosomes of AA compared to EA. In addition to that CD47 and SIRP-α (Signal Regulatory Protein) are highly expressed in Kaiso-scrambled MDA-MB-231 cells (sh-SCR) and exosomes, whereas THBS1, which is a regulator of CD47 expression and is regarded as angiogenesis inhibitor is significantly increased in sh-Kaiso MDA-231 cells and exosomes. Additionally, we observed that Kaiso directly binds methylated sequences in the promoter region of CD47 and THBS1 by ChIP assay. Furthermore, in vivo sh-Kaiso cells injected into athymic mice exhibited delayed tumor formation after four weeks with smaller tumor size as compared to sh-SCR cells, and we observed higher expression of THBS1 with lower expression of CD47 and SIRP-α molecules by IHC and exosomes isolated from invivo tumors, indicating that Kaiso is associated with macrophage mediated immune escape.
Conclusion: Our findings demonstrate the role of kaiso in immune signaling through exosomes which may be related with more aggressive cancer phenotype in breast cancer specially in African Americans.
Citation Format: Md Shakir U. Ahmed, Brittany Jenkins, Benjamin Adu-Addai, Balasubramanyam Karanam, Melissa B. Davis, William E. Grizzle, Honghe Wang, Clayton C. Yates. Kaiso influences immune signaling of breast cancer exosomes [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 1525.
Abstract 1527: Intraperitoneal myeloid-derived suppressor cells in peritoneal dissemination mouse model
Authors: Sugita Yutaka , Yamashita Kimihiro , Takimoto Rishu , Tanaka Tomoko , Arimoto Akira , Fukuoka Eiji , Nakamura Tetsu , Suzuki Satoshi , Kakeji Yoshihiro 
Published: August 2019

Abstract
Background: Myeroid-derived suppressor cells (MDSCs) are heterogeneous cell populations derived from bone marrow, and two subsets of M-MDSC and PMN-MDSC are known in mice. They accumulate in the tumor-bearing host, and suppresse cell-mediated immunity mainly on T cells, and inhibit anti-tumor immune responses. We have previously reported that (1) the increase of MDSCs in lung, peripheral blood, and spleen reflects the cancer progression, (2) MDSCs in peripheral blood would be useful as a marker of recurrence as it increases in recurrent cases after surgical resection. On the other hand, no detailed report on the dynamics of intraperitoneal MDSCs has been made. In this study, we made peritoneal dissemination mouse models and monitored intraperitoneal MDSCs, and investigated whether MDSCs are involved in the progression of peritoneal dissemination.
Methods: MC38 colon cancer cell line was intraperitoneally injected to C57BL / 6J mice and the change in the number and ratio of immune cells (MDSC, Macrophage, T-cell, B-cell) in the spleen, peripheral blood and peritoneal cavity was monitored over time. We examined the correlation between transition of immune cells and cancer progression.
Results: MDSCs increased with cancer progression in all spleen, peripheral blood, and intraperitoneal cavity. The proportion of PMN-MDSCs in MDSCs increased in peripheral blood. In contrast, the proportion of M-MDSCs increased initially, then the PMN-MDSCs increased in the abdominal cavity.
Conclusion: Intraperitoneal MDSCs were thought to reflect the progression of peritoneal dissemination as well as spleen and peripheral blood. The proportion of M-MDSCs reflects the disease state in the microperitoneal dissemination with serous ascitic fluid, and ascites became bloody and the proportion of PMN-MDSCs increased with the progression of seeding. We are examining treatment for peritoneal dissemination with this feature in mind.
Citation Format: Yutaka Sugita, Kimihiro Yamashita, Rishu Takimoto, Tomoko Tanaka, Akira Arimoto, Eiji Fukuoka, Tetsu Nakamura, Satoshi Suzuki, Yoshihiro Kakeji. Intraperitoneal myeloid-derived suppressor cells in peritoneal dissemination mouse 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 1527.
Abstract 1542: Bispecific T cell engager-induced toxicity in an immunocompetent solid tumor model
Authors: Godbersen-Palmer Claire , Coupet Tiffany , Grada Zakaria , Sentman Charles 
Published: August 2019

Abstract
Chimeric antigen receptor (CAR) T cells and bispecific T cell engagers have demonstrated clinical efficacy, however are often accompanied by severe toxicity including cytokine release syndrome (CRS), neurotoxicity or macrophage activation syndrome (MAS). Mechanistic understanding of the development of these toxicities and testing of therapeutic interventions is limited by a lack of suitable immunocompetent pre-clinical models. We have developed both human and murine versions of a bispecific molecule with specific activity against target expressing tumor cells in vitro and in vivo. These bispecific proteins are constructed from the extracellular portion of either mouse or human NKG2D receptor and target cells expressing the cognate ligands by redirecting T cells through their CD3 binding arm. Using the murine bispecific protein, mNKG2DxCD3, we have developed an immunocompetent mouse tumor model which exhibits treatment induced toxicity and recapitulates key features similar to those observed in human CRS. Toxicity was observed between the 2nd and 4th bispecific protein injections but was not observed following subsequent injections. Monitoring of toxicity kinetics showed transient symptoms peaking 3-4 hours following bispecific protein injection with complete resolution after 8 hours. Weight loss and elevated plasma cytokines including IFNγ, IL6, TNFα, IL2 and IL10 were also associated with toxicity. Pathology analysis showed a reduction in white pulp in the mouse spleens, however, other organs evaluated (brain, kidney, lung and heart) were normal. Using mouse genetic knockout models, we were able to show that T cells, IFNγ and Perforin were required for development of this toxicity. Additionally, In vivo depletion of either CD4+ or CD8+ T cells was sufficient to prevent the onset of toxicity. These findings highlight the importance of T cell activation and function and shed light on the mechanistic underpinnings of bispecific T cell engager protein induced toxicity.
Citation Format: Claire Godbersen-Palmer, Tiffany Coupet, Zakaria Grada, Charles Sentman. Bispecific T cell engager-induced toxicity in an immunocompetent solid 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 1542.
Abstract 1547: DNA-encoded bispecific T-cell engagers and antibodies present long-term antitumor activity
Authors: Perales-Puchalt Alfredo , Duperret Elizabeth K. , Muthumani Kar , Weiner David B. , Yang Xue , Zhu Xizhou , Wojtak Krzysztof , Tello-Ruiz Edgar , Wise Megan C. 
Published: August 2019

Abstract
Specific antibody therapy, including monoclonal antibodies and bispecific T cell engagers (BiTEs), are important new tools for cancer immunotherapy. However, these approaches are slow to develop and may be limited in their production thus restricting the patients who can access these treatments. BiTEs exhibit a particularly short half-life and difficult production. The development of an approach allowing simplified development, delivery and in vivo production would be an important advance. Here we describe development of a designed synthetic DNA plasmid, which we optimized to permit high expression of an anti-HER2 antibody (HER2DMAb) and delivered it into animals through adaptive electroporation. HER2DMAb was efficiently expressed in vitro and in vivo, reaching levels of 50ug/ml in mouse sera. Mechanistically, HER2DMAb blocked HER2 signaling and induced antibody-dependent cytotoxicity. HER2DMAb delayed tumor progression for HER2-expressing ovarian and breast cancer models. We next used the HER2DMAb scFv portion to engineer a DNA-encoded BiTE. This HER2DBiTE was expressed in vivo for approximately 4 months after a single administration. The HER2DBiTE was highly cytolytic and delayed cancer progression in mice. These studies illustrate a novel approach to generate DBiTEs in vivo which represent promising immunotherapies for HER2+ tumors including ovarian and potentially other cancers.
Citation Format: Alfredo Perales-Puchalt, Elizabeth K. Duperret, Kar Muthumani, David B. Weiner, Xue Yang, Xizhou Zhu, Krzysztof Wojtak, Edgar Tello-Ruiz, Megan C. Wise. DNA-encoded bispecific T-cell engagers and antibodies present long-term antitumor activity [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 1547.