bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B37: Dissecting the playbook of cancer: Genomic analysis of 100,000 human tumors reveals elaborate patterns of activation of the RTK-RAS-MAPK pathway
Authors: Manning Gerard , Lounsbury Nicholas , Hartmaier Ryan , Trabucco Sally , Sokol Ethan , Rinaldi Jacob , Liu Jinfeng , Gnad Florian 
Published: February 2019

Abstract
This abstract is being presented as a short talk in the scientific program. A full abstract is printed in the Proffered Abstracts section (PR03) of the Conference Proceedings.
Citation Format: Gerard Manning, Nicholas Lounsbury, Ryan Hartmaier, Sally Trabucco, Ethan Sokol, Jacob Rinaldi, Jinfeng Liu, Florian Gnad. Dissecting the playbook of cancer: Genomic analysis of 100,000 human tumors reveals elaborate patterns of activation of the RTK-RAS-MAPK pathway [abstract]. In: Proceedings of the Fifth AACR-IASLC International Joint Conference: Lung Cancer Translational Science from the Bench to the Clinic; Jan 8-11, 2018; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(17_Suppl):Abstract nr B37.
Abstract A061: STING, an immune biomarker for colorectal cancer
Authors: Chon Hongjae , Kim Chan 
Published: February 2019

Abstract
Background: STING is an innate immune sensor for cytosolic DNA. The activation of STING signaling is indispensable in Type I interferon response and the evocation of anticancer immune response by CD8+ T-cells. The aim of this study is to characterize intratumoral STING expression pattern and its clinical implication in colorectal cancer (CRC). Methods: We analyzed STING and CD8 expression in 225 CRC patients who underwent surgical resection. Clinicopathologic variables and survival outcomes were analyzed according to STING expression level. Results: Distinct STING expression was observed in tumor specimens of CRCs. Patients with higher STING expression seemed to have early stage cancer (P = 0.001) with increased intratumoral CD8+ T-cell infiltration (P &lt; 0.001), and less frequent lymphovascular invasion (P = 0.02). Compared to CRC patients with lower STING expression, those with higher STING expression had longer overall survival (P &lt; 0.001) and recurrence-free survival (P &lt; 0.001). The Cox proportional hazard model, adjusted for age, stage, and CD8+ T-cells, revealed that higher STING expression is an independent prognostic factor for a better overall survival (P = 0.012, hazard ratio 0.573, 95% CI 0.370 – 0.886). Conclusion: We have confirmed the distinct STING expression in CRC and demonstrated its independent prognostic value for the survival outcome, thereby suggesting the intratumoral STING expression as a potential immune biomarker for CRC.
Citation Format: Hongjae Chon, Chan Kim. STING, an immune biomarker for colorectal cancer [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A061.
Abstract A067: Cognate interaction with CD4+ T-cells instructs M2-like macrophages to acquire M1-like phenotype
Authors: Eisel David , Osen Wolfram , Das Krishna , Hoerhold Franziska Marie-Claire , König Rainer , Eichmüller Stefan B. 
Published: February 2019

Abstract
Current tumor immunotherapy approaches are based on application of checkpoint inhibitors, such as monoclonal antibodies against PD-1/PD-L1 and CTLA-4 or adoptive T-cell therapy using ex vivo expanded TILs or genetically modified autologous T-cells expressing recombinant T-cell receptors (TCRs) or chimeric antigen receptors (CARs). However, the success of these therapeutic strategies is often limited by various inhibitory immune cell types accumulating in the tumor. In particular, tumor-associated macrophages (TAMs) contribute to the immune suppressive tumor micro-milieu, since so-called M2-like macrophages suppress the function of T effector cells and promote the differentiation of regulatory T-cells (Treg) through secretion of inhibitory cytokines such as TGF-β and IL10. Tumor antigen-specific CD4+ T effector cells, on the other hand, can essentially sustain antitumoral immune responses as shown for various tumor entities. In fact, using peritoneal exudate cells (PECs) as source for macrophages we demonstrate that MHC II restricted interaction between ovalbumin (OVA) specific CD4+ T-cells and M2-like macrophages drives M1 polarization. This was confirmed by detailed gene and protein expression analyses as well as functional assays testing phagocytic and pinocytic activities of repolarized macrophages. Moreover, in a set of preclinical experiments, adoptive transfer of CD4+, OVA-specific OT-II cells into C57BL/6 mice bearing OVA expressing IAb-/- tumors resulted in increased intratumoral number of M1-like TAMs as determined by gene expression analysis and flow cytometry. Furthermore, we observed a significant survival benefit of mice treated with a combination of OVA-specific CD4+ (OT-II) and CD8+ (OT-I) cells after transplantation of B16F10-Ova tumors and a complete response in some mice that rejected the tumor cells also upon a later re-challenge. While the antitumoral effect of this adoptive transfer experiment has been already described, we now offer a possible explanation for the supportive effect of specific CD4+ cells on co-transferred CD8+ cells. Taken together, the instructive impact of CD4+ T-cells on M2-like macrophages described in this presentation points towards a so far underestimated function of the CD4+ T-cell / TAM axis in reconditioning the immunosuppressive tumor micro-milieu.
Citation Format: David Eisel, Wolfram Osen, Krishna Das, Franziska Marie-Claire Hoerhold, Rainer König, Stefan B. Eichmüller. Cognate interaction with CD4+ T-cells instructs M2-like macrophages to acquire M1-like phenotype [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A067.
Abstract A087: The immunosuppressive property of mesenchymal stem cell in an apoptotic tumor microenvironment
Authors: Li Anita K.Y. , Cao Carmen J.M. , Chan Godfrey C.F. 
Published: February 2019

Abstract
Mesenchymal stem cells (MSCs) are a heterogeneous population of multipotenT-cells and are capable of differentiating into certain cell types. They can be found within tumor core and constitute part of the tumor microenvironment. Their role in tumor progression remains contradictory with both sides arguing pro- and anti-tumor function. In regarding to the pro-tumor effect, MSCs have shown to have immunoregulatory properties—suppressing T lymphocytes, B lymphocytes and dendritic cells, thereby helping tumor cells to escape from the immune surveillance. However there are some studies that showed certain microenvironment and stimulation can drive MSC into a proinflammatory phenotype. During cancer therapy, large amount of apoptotic cells are released to the tumor microenvironment. The aim of this study is to investigate how an apoptotic microenvironment can affect the function of MSC on naïve T-cells. Apoptotic cells (ACs) were derived from the neuroblastoma cell line SK-N-LP treated with cisplatin for 24 hr; they were then co-cultured with the immortalised human MSC cell line (hTMSC). Naïve T-cells were isolated from peripheral blood mononuclear cells of healthy donors and further co-cultured with either hTMSC alone or AC-treated hTMSC (hTMSC-AC) for 5 days. Cell proliferation and phenotype were analyzed by flow cytometry. We demonstrated that hTMSCs have the ability to phagocytose AC. After engulfment, the hTMSC-AC were able to increase T-cell proliferation compared to those co-cultured with untreated hTMSC. The T-cells co-cultured with hTMSC-AC also showed a decrease in CD45RA expression, suggesting an increase in T-cell activation. Moreover, these T-cells had a higher expression level of interferon-gamma (IFN-γ) and a lower expression of FoxP3, indicating a shift towards proinflammatory effector T-cells and a reduction of regulatory T-cells. Consistent with other literature, hTMSC has the ability to supress T-cells’ activation and proliferation. However in the presence of AC, hTMSC immunosuppressive property was impeded, thereby heightening the immune response. Therefore the microenvironment can play a major factor in determining the role of MSC on tumor. Further investigation of the interaction of MSC with immune cells in an apoptotic tumor microenvironment can lead to a potential immunotherapy for neuroblastoma.
Citation Format: Anita K.Y. Li, Carmen J.M. Cao, Godfrey C.F. Chan. The immunosuppressive property of mesenchymal stem cell in an apoptotic tumor microenvironment [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A087.
Abstract A093: Immune resistance emerges from tumor-initiating stem cells
Authors: Miao Yuxuan , Fuchs Elaine 
Published: February 2019

Abstract
Stem cells have a remarkable capacity to self-renew, generate and repair tissues. Their long lifespan leaves stem cells vulnerable to acquiring mutations, which over time can cause them to initiate and propagate a tumor. These cancer stem cells (CSC) are endowed with many unique molecular features to drive tumorigenesis, as well as to promote resistance to cancer therapies. However, whether there are any specialized mechanisms enabling the cancer stem cells to overcome immune surveillance remains poorly understood. In this study, we designed a skin squamous cell carcinoma cancer model that can be effectively challenged by adoptive cell transfer (ACT)-based immunotherapy. By single cell-RNA-seq profiling the molecular signature and lineage-tracing the fate of any cancer cells that survive the ACT treatment, we discovered that a group of TGF-β responding CSCs resist ACT, resulting in tumor relapse. Probing mechanism, we found that during malignancy, CSCs selectively acquire CD80. Thought to be an immune cell ligand, stem cell CD80 engagement with Cytotoxic T lymphocyte antigen-4 (CTLA4) on activated cytotoxic T-cells attenuates their attack, and upon CD80 ablation or CTLA4 immunotherapy, CSCs become vulnerable, reducing tumor burden. Our findings place CSCs at the crux of how immune checkpoint pathways are activated.
Citation Format: Yuxuan Miao, Elaine Fuchs. Immune resistance emerges from tumor-initiating stem cells [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A093.
Abstract A118: Clinical impact of PD-L1 expression and epithelial-mesenchymal transition in the tumor microenvironment of extrahepatic cholangiocarcinoma
Authors: Tsuchikawa Takahiro , Ueno Takashi , Sato Osamu , Nakamura Toru , Nakanishi Yoshitsugu , Asano Toshimichi , Noji Takehiro , Okamura Keisuke , Shichinohe Toshiaki , Hirano Satoshi 
Published: February 2019

Abstract
Background: Extrahepatic cholangiocarcinoma (eCCA) has a poor prognosis. Although the possibility of immunotherapy has been studied, immune checkpoint molecules such as programmed death ligand 1 (PD-L1) in eCCA are not well understood. Epithelial-mesenchymal transition (EMT) has recently been shown to regulate PD-L1 expression. Our aims were to assess the clinicopathological significance of tumor-infiltrating lymphocytes (TILs) and tumor PD-L1 expression in eCCA and to compare these immune responses with EMT marker expression. Material and Methods: An immunohistochemical evaluation using a TMA method at a single large center was performed. Patients (n = 117) underwent surgical resection in the Department of Gastroenterological Surgery II at Hokkaido University Hospital between January 1995 and November 2006 and eCCA tumors were confirmed histopathologically. We investigated the level of infiltration of immune cells positive for CD4, CD8, Foxp3, PD-L1 in addition to E-cadherin, N-cadherin, Vimentin, ZEB1, ZEB2, SNAIL, TWIST expression, statistically comparing correlations among these factors. Results: High numbers of CD4+ and CD8+ TILs correlated with node-negative (P = 0.009 and P = 0.046, respectively) and low SNAIL expression (P = 0.016 and P = 0.022, respectively). High PD-L1 expression was associated with poor histopathologic classification (P = 0.034), and low E-cadherin (P = 0.001), high N-cadherin (P = 0.044), high vimentin (P &lt; 0.001) and high ZEB1 (P = 0.036) expression. Multivariate analysis showed that CD4+ TILs, PD-L1 expression and N-cadherin expression were independent prognostic factors (hazard ratio (HR) = 0.61; 95% confidence interval (CI) = 0.38-1.00; HR=4.27; 95% CI = 1.82-9.39; HR = 2.20; 95% CI = 1.18-3.92, respectively). Summary: Present data suggested that CD4+ T lymphocyte tumor infiltration and PD-L1 expression on tumor cells were independent prognostic factors in eCCA. We also provided the first evidence that high tumor PD-L1 expression correlates with a mesenchymal phenotype.
Citation Format: Takahiro Tsuchikawa, Takashi Ueno, Osamu Sato, Toru Nakamura, Yoshitsugu Nakanishi, Toshimichi Asano, Takehiro Noji, Keisuke Okamura, Toshiaki Shichinohe, Satoshi Hirano. Clinical impact of PD-L1 expression and epithelial-mesenchymal transition in the tumor microenvironment of extrahepatic cholangiocarcinoma [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A118.
Abstract A120: Intratumoral dendritic cell dynamics in responsive and nonresponsive syngeneic murine tumor models
Authors: Xiong Huizhong , Mittman Stephanie , Rodriguez Ryan , Moskalenko Marina , Sanchez Patricia Pacheco , Yang Yagai , Cubas Rafael 
Published: February 2019

Abstract
Conventional dendritic cells (cDC) play a vital role in T-cell-mediated antitumor immunity by transporting and cross-presenting tumor antigens to CD8 T-cells in draining lymph nodes (dLN) and tumor tissue. DC maturation and antigen uptake takes place in the tumor, which can be heavily affected by the suppressive tumor microenvironment. Intratumoral DCs are a scarce population and their phenotypes and functions have not been fully understood. Here we thoroughly characterized cDC phenotypes and dynamics in a variety of commonly used syngeneic murine tumor models, both at baseline and following anti-PD-L1 (aPDL1) treatment to investigate the correlation and potential contribution of DCs to response. Surprisingly, we observed a lower density of intratumoral DCs in responsive tumor models when compared to nonresponsive ones and their abundance was further reduced by aPDL1 treatment in an IFNg-dependent manner. Their PDL1 expression levels, albeit lower than tumor macrophages, were positively correlated with response. These results demonstrate an inverse correlation between intratumoral DCs and aPDL1-mediated antitumor immunity across different syngeneic murine tumor models, and ongoing studies are exploring the fates of these intratumoral DCs with a focus on their causal relation with the efficacy of immunotherapy.
Citation Format: Huizhong Xiong, Stephanie Mittman, Ryan Rodriguez, Marina Moskalenko, Patricia Pacheco Sanchez, Yagai Yang, Rafael Cubas. Intratumoral dendritic cell dynamics in responsive and nonresponsive syngeneic murine tumor models [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A120.
Abstract A121: Single-cell transcriptomic analyses reveal heterogeneity of vascular endothelial cells in cancer models
Authors: Zhu Yu , Salazar Nicole , Brulois Kevin , Butcher Eugene 
Published: February 2019

Abstract
The immune system has demonstrated promising potential as a therapeutic target in the treatment of certain cancer types, yet in many tumors the efficacy of immunotherapies is still extremely poor. One major obstacle is the limited access of immune cells to the tumor tissue. The tumor vasculature plays critical roles in regulating the recruitment of anti-tumor immune cells and the delivery of immunotherapies to the tumor sites. These immune processes require functional specialization of endothelial cells (ECs). However, there is a major gap in our understanding of the diversity, molecular specialization, and developmental relationships of tumor-associated EC subsets. To understand the heterogeneity of tumor-associated endothelium, we performed single-cell RNA sequencing (scRNAseq) analyses on ECs isolated from mouse cancer models. scRNAseq identified several subsets of endothelium in the tumor tissue, including ECs that compose the artery, capillary, and post-capillary venules. Interestingly, within the capillary endothelial compartment, we identified an EC subset that resembles tip cells in sprouting angiogenesis and demonstrates molecular signature of stem or progenitor cells. These putative progenitor cells are dramatically expanded in tumors compared to normal tissues, and comprise both quiescent and proliferative populations. The quiescent ECs express high levels of genes coding for antiapoptotic proteins, extracellular matrix molecules, immune checkpoint molecules, monocyte/macrophage recruiting cytokines, and stem cell signaling components, such as Notch4. On the other hand, the proliferative tip-like ECs express genes coding for cyclins and cyclin-dependent kinases, DNA damage repair molecules, necroptosis machinery, and epigenetic regulators. Taken together, these data define the heterogeneity of tumor-associated endothelial cells, and reveal a putative progenitor population that gives rise to the tumor vasculature and could be targeted to improve the efficacy of immunotherapies.
Citation Format: Yu Zhu, Nicole Salazar, Kevin Brulois, Eugene Butcher. Single-cell transcriptomic analyses reveal heterogeneity of vascular endothelial cells in cancer models [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A121.
Abstract A132: Identification of pyroptosis inhibitors that target a reactive cysteine in gasdermin D
Authors: Hu Jun , Liu Xing , Zhao Jingxia , Xia Shiyu , Ruan Jianbin , Luo Xuemei , Kim Justin , Lieberman Judy , Wu Hao 
Published: February 2019

Abstract
Inflammasomes are multiprotein signaling scaffolds that assemble in response to invasive pathogens and sterile danger signals to activate inflammatory caspases (1/4/5/11), which trigger inflammatory death (pyroptosis) and processing and release of proinflammatory cytokines. Inflammasome activation contributes to many human diseases, including inflammatory bowel disease, gout, type II diabetes, cardiovascular disease, Alzheimer’s disease, and sepsis, the often fatal response to systemic infection. The recent identification of the pore-forming protein gasdermin D (GSDMD) as the final pyroptosis executioner downstream of inflammasome activation presents an attractive drug target for these diseases. Here we show that C-23 and C-27 potently inhibit GSDMD pore formation in liposomes and inflammasome-mediated pyroptosis and IL-1β secretion in human and mouse cells. Moreover, C-23, administered at a clinically well-tolerated dose, inhibits LPS-induced septic death and IL-1β secretion in mice. Both compounds covalently modify a conserved Cys (Cys191 in human and Cys192 in mouse GSDMD) that is critical for pore formation. Inflammatory caspases employ Cys active sites, and many previously identified inhibitors of inflammatory mediators, including those against NLRP3 and NF-κB, covalently modify reactive cysteine residues. Since NLRP3 and noncanonical inflammasome activation are amplified by cellular oxidative stress, these redox-sensitive reactive cysteine residues may regulate inflammation endogenously, and compounds that covalently modify reactive cysteines may inhibit inflammation by acting at multiple steps. Indeed, both C-23 and C-27 also directly inhibit inflammatory caspases and pleiotropically suppress multiple processes in inflammation triggered by both canonical and noncanonical inflammasomes, including priming, puncta formation and caspase activation. Hence, cysteine-reactive compounds, despite their lack of specificity, may be attractive agents for reducing inflammation.
Citation Format: Jun Hu, Xing Liu, Jingxia Zhao, Shiyu Xia, Jianbin Ruan, Xuemei Luo, Justin Kim, Judy Lieberman, Hao Wu. Identification of pyroptosis inhibitors that target a reactive cysteine in gasdermin D [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A132.
Abstract A133: APOBEC3 confers resistance to oncolytic VSV therapy
Authors: Huff Amanda L. , Wongthida Phonphimon , Kottke Timothy , Thompson Jill , Driscoll Christopher B. , Schuelke Matthew , Shim Kevin G. , Harris Reuben S. , Molan Amy , Pulido Jose S. , Selby Peter J. , Harrington Kevin J. , Melcher Alan , Evgin Laura , Vile Richard 
Published: February 2019

Abstract
Tumor cells are able to evade cytotoxic therapies through the accumulation of genomic mutations and rapid evolution. In the case of oncolytic virotherapy, understanding the mechanisms by which cancer cells develop resistance to infection and lysis is critical to the development of more effective viral-based platforms. Here, we identify APOBEC3 as an important factor involved in the restriction of vesicular stomatitis virus (VSV). We show that VSV infection of B16 murine melanoma cells upregulated APOBEC3 in an IFNβ-dependent manner, which was responsible for the evolution of virus-resistanT-cell populations and suggested that APOBEC3 expression promoted the acquisition of a virus-resistant phenotype. ShRNA knockdown of APOBEC3 in B16 cells diminished their capacity to develop resistance to VSV infection in vitro, and enhanced the therapeutic effect of VSV in vivo. Similarly, overexpression of human APOBEC3B promoted the acquisition of resistance to oncolytic VSV in murine melanoma and glioblastoma lines, as well as in a human melanoma cell line in vitro and in vivo. Finally, we demonstrate that progeny virus obtained after passage through APOBEC3B overexpressing cells contained more defective interfering particles, thereby indicating that APOBEC3B directly affected the fitness of VSV, an RNA virus that has not previously been identified to be restricted by APOBEC3B. This research identifies APOBEC3 enzymes as key players to target in order to improve the efficacy of oncolytic viruses as well as broader nucleic acid-based therapeutic platforms.
Citation Format: Amanda L. Huff, Phonphimon Wongthida, Timothy Kottke, Jill Thompson, Christopher B. Driscoll, Matthew Schuelke, Kevin G. Shim, Reuben S. Harris, Amy Molan, Jose S. Pulido, Peter J. Selby, Kevin J. Harrington, Alan Melcher, Laura Evgin, Richard Vile. APOBEC3 confers resistance to oncolytic VSV therapy [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A133.