bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4940: The clinical significance of MRE11 expression based on location of primary tumor in colorectal cancer patients: an integrative analysis of multi-center data
Authors: Fan Chuanwen , Kopsida Maria , Liu Youbin , Zhang Hong , Gao Jingfang , Arbman Gunnar , Cao Siyuwei , Li Yuan , Zhou Zongguang , Sun Xiaofeng 
Published: August 2019

Abstract
MRE11 plays an important role in DNA damage response for maintenance of genome stability and is becoming a prognostic marker. Its role, however, remains controversial in colorectal cancer (CRC) as it we don’t know if this difference is caused by the different locations of primary cancer. To figure out the prognostic heterogeneity of MRE11 in CRC, 207 primary CRC samples from Swedish, as well as 596 primary CRC samples from TCGA data were included in present study. The associations of MRE11 expression against tumor-infiltrating inflammatory cells (TIICs) and microsatellite status with overall survival in right-sided CRC (RSCRC) and left-sided CRC (LSCRC) were assessed. The weighed gene co-expression network analysis and ClueGO were adopted to further analyze the different signaling of MRE11-related in RSCRC and LSCRC. The results showd that either high MRE11 expression alone (HR = 0.37, 95% CI = 0.18-0.76, P = 0.007) or the combination of high MRE11 expression with high TIICs was related to a favorable prognosis (HR = 0.150, 95% CI = 0.043-0.524, P = 0.003) in LSCRC. High MRE11 expression associated with a favorable prognosis in LSCRC with microsatellite stability (HR = 0.23, 95% CI = 0.09-0.55, P = 0.001). The relationships furnished above were adjusted for TNM stage, differentiation and/or TIICs, and no such evidence was present in RSCRC. Further analysis of the biological functions and the pathway involving MRE11 was associated with cell cycle process and DNA repair in both RSCRC (cor = 0.55, P = 0.55e-46) and LSCRC (cor = 0.62, P = 3e-64), whereas, activation of the immune response, necrotic cell death specifically correlated with LSCRC (cor = 0.5, P = 8e-38). In Conclusions, High MRE11 expression is associated with a favorable prognosis and the enhanced prognostic potency of combining high MRE11 with high TIICs in LSCRC. The prognostic heterogeneity of MRE11 in CRC may be due to the differential cell signals activated by MRE11 in RSCRC and LSCRC. The prognostic heterogeneity of MRE11 provides a novel rationale for stratifying patients accordingly, in order to obtain a better personalized prognostic evaluation for CRC patients.
Citation Format: Chuanwen Fan, Maria Kopsida, Youbin Liu, Hong Zhang, Jingfang Gao, Gunnar Arbman, Siyuwei Cao, Yuan Li, Zongguang Zhou, Xiaofeng Sun. The clinical significance of MRE11 expression based on location of primary tumor in colorectal cancer patients: an integrative analysis of multi-center data [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 4940.
Abstract 4943: Leveraging single-cell sequencing to discover novel exhaustion markers of CD8 T cells
Authors: Shi Xiaoshan , Jayaram Savita , Lee Kayla , Bhojak Keshav , Kode Vasumathi , Chaudhary Mridul , Patil Ashwini , Gupta Ravi , Chaudhuri Amit , Chakraborty Papia 
Published: August 2019

Abstract
Therapeutic revival of tumor-specific exhausted T cells using checkpoint blockade antibodies has improved clinical outcomes in cancer significantly. Notwithstanding a high overall response rate to these drugs, long-term benefit is realized by a small fraction of the treated patients. A mechanistic explanation of relapse comes from the recent findings that in both murine and human cancers intratumoral T cells exist in a wide spectrum of functional states – from fully functional at one end of the spectrum, to fully dysfunctional at the other end. Therefore, tumor response to checkpoint inhibitors is determined by the ratio of functional to dysfunctional state of T cells, which in turn is modulated by a wide array of immune-suppressive signals present within the tumor microenvironment. Dissecting the T cell functional states can significantly enhance our understanding of patient responses to immunotherapy drugs and can be used to develop targeted and personalized strategies for restoring antitumor immunity. A key challenge to this problem is that the transcriptional signatures of dysfunctional exhausted T cells are closely intertwined with the activated/effector CD8+ T cell states. This is not surprising, since T cell dysfunction arises following chronic T cell activation. Developing unique markers of T cell exhaustion from in vivo models has not been successful. In this study, we present data to show how single cell transcriptomics on a 10x Genomics platform can identify T cell functional states following antigen-stimulation in an ex vivo T cell activation system. In particular, we identified functional gene clusters and molecular networks that are unique to CD8+ T cell exhausted state. The combined expression of our T cell exhaustion gene signature correlated with poor prognosis when applied to TCGA data of over 1500 tumors from many different cancers. Furthermore, the molecular pathways identified in this study provide opportunities to develop novel therapeutic interventions specially targeting dysfunctional T cells in cancers thereby enhancing the efficacy of checkpoint inhibitors.
Citation Format: Xiaoshan Shi, Savita Jayaram, Kayla Lee, Keshav Bhojak, Vasumathi Kode, Mridul Chaudhary, Ashwini Patil, Ravi Gupta, Amit Chaudhuri, Papia Chakraborty. Leveraging single-cell sequencing to discover novel exhaustion markers of CD8 T 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 4943.
Abstract 4944: Differential expression of complex immune biology in MSI and MSS colorectal tumor microenvironments using high-plex spatial resolution
Authors: Fuhrman Kit , Church Sarah , Zolligner Daniel , Reeves Jason , Hinerfeld Doug , Bailey Christina , Warren Sarah 
Published: August 2019

Abstract
Spatial characterization of the tumor microenvironment (TME) including cancer cells, stroma and immune cells is essential for understanding tumor progression and discovering prognostic and predictive biomarkers. However, it has proven difficult to perform such studies in a highly multiplexed manner using limited sample quantity. GeoMx™ Digital Spatial Profiling (DSP) has been developed as an integrated research use platform for hi-plex spatial profiling of mRNA and protein using an optical-barcode read-out without the need for on-tissue molecular biology. In this study, we combined both bulk gene expression analysis using the NanoString PanCancer IO360™ panel and the spatial analysis of 40 proteins and 78 RNAs to characterize microsatellite stable (MSS) or instable (MSI) colorectal tumors to evaluate active and suppressive immune mechanisms in both immune dense regions and tumor versus stroma.
Comparing colorectal tumors characterized by MSS, spatial analysis of RNA and protein expression by DSP was able to differentiate immune hot and cold regions of the tumors despite MSS status. Furthermore, comparison of immune-enriched hot-spots, measured by CD45 dense regions of interest, showed that MSS immune hot tumors had decreased macrophage and tumor proliferation markers compared to MSI immune hot tumors, elucidating potential therapeutic targets. Since there is a subset of patients with MSS colorectal cancer that still responds to immunotherapy, this suggests DSP could ultimately be used to identify unique spatial biology and immune characteristics that might further expand beyond MSS and MSI status and tradition gene signatures to help predict patients' response to mono- or combination therapy.
Citation Format: Kit Fuhrman, Sarah Church, Daniel Zolligner, Jason Reeves, Doug Hinerfeld, Christina Bailey, Sarah Warren. Differential expression of complex immune biology in MSI and MSS colorectal tumor microenvironments using high-plex spatial resolution [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 4944.
Abstract 4948: T helper 2 cells block breast cancer promotion
Authors: Boieri Margherita , Malishkevich Anna , Steidl Lauren , Ngo Kenneth , Iyer Sowmya , Awad Mary , Kreuzer Johannes , Haas Wilhelm , Rivera Miguel , Demehri Shadmehr 
Published: August 2019

Abstract
New immune-based strategies for cancer treatment including the activation of tumor-infiltrating CD8+ cytotoxic T lymphocytes (CTLs) have led to effective therapeutics against late-stage disease. However, the function of the immune system in combating the early-stage cancers remains uncertain. To establish a mechanism that activates immune cells against early carcinogenesis, we have studied the role of an epithelial-derived cytokine, thymic stromal lymphopoietin (TSLP), in early stages of breast cancer development. We have previously discovered that TSLP blocks breast carcinogenesis through the activation of CD4+ T cells that heavily infiltrate the sites of developing cancer in the breast gland without affecting the normal tissue.To investigate the mechanism by which TSLP-stimulated CD4+ T cells suppress spontaneous breast cancer development, we used MMTV-PyMT transgenic mouse models (PyMTtg) that spontaneously develop breast tumors and resemble the human luminal breast cancer. These mice were crossed into TSLP transgenic mice that produce TSLP under the promoter of a skin-specific keratin 14 promoter (K14-TSLPtg), plus additional knockouts including TSLPR-/- and IL4rα;-/-. Tumor development was arrested in K14-TSLPtg;PyMTtg mice compared to PyMTtg counterparts as their tumors failed to progress to high grade. The tumor suppressive mechanism of CD4+ T cells was mediated by a block in cancer cell proliferation, but not by cytotoxicity. Polarization of CD4+ T cells into T helper 2 (Th2) subtype was essential for blocking breast tumor development, and the tumor suppression was achieved by CD4+ T cells in the absence of CD8+ T and B cells. Finally, we found the basal levels of TSLP released by premalignant breast epithelial cells to be protective against the early phases of breast cancer development.In conclusion, we demonstrate that CD4+ Th2 cells block early stages of breast carcinogenesis. TSLP stimulated CD4+ Th2 cells induce an arrest in cancer cell proliferation, which represents a novel mode of immunity with great potential for the prevention and treatment of breast cancer.
Citation Format: Margherita Boieri, Anna Malishkevich, Lauren Steidl, Kenneth Ngo, Sowmya Iyer, Mary Awad, Johannes Kreuzer, Wilhelm Haas, Miguel Rivera, Shadmehr Demehri. T helper 2 cells block breast cancer promotion [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 4948.
Abstract 4951: Obesity-induced changes in baseline immune responses to pre-clinical breast cancer
Authors: Gibson Justin , Nagareddy Prabhakara , Norian Lyse 
Published: August 2019

Abstract
Obesity is known to increase morbidity and mortality in breast cancer patients; however, the immunological contributions to such changes remain incompletely understood. Our long-term goal is to investigate the broad impact of obesity on anti-tumor immunity, with a particular focus on understanding the mechanisms underlying obesity-induced immune alterations and how these alterations may influence the use of immunotherapeutics in breast cancer patients. For our studies, we utilized a diet-induced model of obesity (DIO) in which mice were fed either a high-fat or low-fat diet to generate DIO or age-matched lean controls, respectively. Animals were then challenged with the syngeneic E0771 mammary carcinoma cell line. Tumor outgrowth was quantified by caliper measurements, bioluminescent imaging (BLI) via firefly luciferase-expressing E0771 (E0771-fLUC) cells, and endpoint tumor weights. Whole tumor immunogenetic gene expression profiles were evaluated using nanoString and immune populations were assessed via multi-parameter flow cytometry. All measures of tumor outgrowth reveal that obesity significantly increases primary tumor outgrowth and induces a variety of alterations to the immunogenetic profile. Additionally, obesity significantly alters the frequency of intra-tumoral immune populations, including decreases in CD4+ and CD8+ T cells, increases in granulocytic myeloid-derived suppressor cells (G-MDSCs) and myeloid dendritic cells (mDCs), and a trending decrease in total CD45+ tumor infiltrating leukocytes. These alterations are specific to the tumor environment, as they are not present in the spleens of tumor-bearing mice. Collectively these data implicate obesity as a causal agent in impairing anti-tumor immune responses to murine mammary tumors. Furthermore, they suggest several cellular candidates for future mechanistic investigations into obesity-induced alterations in breast cancer immunity.
Citation Format: Justin Gibson, Prabhakara Nagareddy, Lyse Norian. Obesity-induced changes in baseline immune responses to pre-clinical breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4951.
Abstract 4999: Characterization of myeloid derived suppressor cells after capecitabine and nivolumab combination treatment
Authors: Lin Qing , Wang Tienan , Yan Wenjun , Wu Ranran , Nie Lun , Miao Chensi , Wang Xing , Wang Feng , Zhang Jie , Shi Weilin , Yuan Yanping , Shi Tingting , Li Ao , Dong Wei , Chen Xu , Sun Jingying , Ji Qunsheng 
Published: August 2019

Abstract
Capecitabine, a widely used oral chemotherapeutic agent, only functions in its active form, 5-FU. The metabolism of capecitabine to 5-FU frequently occurs in tumor tissues with high expression of thymidine phosphorylase, enzyme responsible for converting capecitabine. Extensive studies have demonstrated that capecitabine functions to inhibit growth of tumors, especially for metastatic breast and colorectal tumors, by impairing DNA synthesis and metabolism. However, effects of capecitabine on myeloid derived suppressor cell (MDSC) in the tumor microenvironment are poorly understood. In fact, conflicting results were reported that capecitabine either reduced CD11bhigh/Gr1high MDSC and enhanced T cell functions, or failed to alter the number and function of MDSC or the levels of GM-CSF/IL6 in blood. In this study, we established an optimized in-vitro MDSC suppressive assay and take the advantage of this system to investigate the function of capecitabine on MDSC-mediated T cell suppression. Myeloid cells in tumor environment acquire the expression of PD-L1, suggesting that blocking the PD1-PD-L1 axis might revert the function of MDSC. Therefore, we further explored the combination effect of capecitabine and nivolumab, a PD-1 antibody, on the function of MDSC in human PBMC cells.
Citation Format: Qing Lin, Tienan Wang, Wenjun Yan, Ranran Wu, Lun Nie, Chensi Miao, Xing Wang, Feng Wang, Jie Zhang, Weilin Shi, Yanping Yuan, Tingting Shi, Ao Li, Wei Dong, Xu Chen, Jingying Sun, Qunsheng Ji. Characterization of myeloid derived suppressor cells after capecitabine and nivolumab combination treatment [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 4999.
Abstract 5022: iGRAMMy: Cloud-based characterization of microbial landscape in colorectal cancers
Authors: Xia Li C. , Ai Dongmei , Guo Man , Ji Hanlee 
Published: August 2019

Abstract
Many studies have identified pervasive tumor-infiltrating bacteria in colon, gastric, kidney, and other tumors. Infiltrating bacteria have functional significance, affecting the immune system state, affecting a tumor’s ability to metastasize, and modifying patient’s response to therapies. Only a few tools can infer infiltrating bacteria based on the RNA-and DNA-Seq data of tumor samples. These tools are not optimized for cloud-based computation, where large public datasets such as The Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium (ICGC) now reside. Here, we present a novel cloud-based bioinformatics tool - iGRAMMy, that accurately, efficiently, and robustly estimate microbial relative abundance in sequenced tumor and matched normal samples. We developed iGRAMMy by integrating read filtering, remapping, and relative abundance estimation steps of whole genome (WGS-seq) and/or transcriptome (RNA-seq) based microbiome analysis. We validated iGRAMMy by comparing estimated abundance to positive and negative controls of a published dataset as golden standard. We applied iGRAMMy to study all colorectal cancer samples within the TCGA cohort and reported the microbial landscape of these tumors. We identified a significantly higher abundance of overall bacterial infiltration in tumor as compared to normal samples. We found species like Bacteroides fragilis, Bacteroides dorei and Fusobacterium nucleatum were significantly higher in tumors, which were corroborated by previous reports. We uniquely identified Bacteroides intestinalis was also significantly more abundant in tumor samples. We released iGRAMMy and the entire analysis as a workflow pipeline on cancer genomics cloud, where researchers can easily replicate the study and use the tool for their own data.
Citation Format: Li C. Xia, Dongmei Ai, Man Guo, Hanlee Ji. iGRAMMy: Cloud-based characterization of microbial landscape in colorectal cancers [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 5022.
Abstract 5024: Treatment with synthetic RIG-I agonist triphosphate RNA leads to local and systemic anti-tumor effects in a mouse melanoma tumor model
Authors: Helms Mike W. , Parmantier Eric , Jahn-Hofmann Kerstin , Gnerlich Felix , König Lars , Metz-Weidmann Christiane , Braun Monika , Dietert Gabriele , Grandien Kaj , Theilhaber Joachim , Cao Hui , Wagenaar Tim , Schnurr Max , Endres Stefan , Wiederschain Dmitri , Scheidler Sabine , Rothenfusser Simon , Brunner Bodo 
Published: August 2019

Abstract
RIG-I is a highly important cytosolic pattern recognition receptor (PRR) involved in sensing RNA virus infection and inducing interferon (IFN) production. RIG-I’s natural ligand, triphosphate RNA (ppp-RNA), is proposed to be a valuable addition to the growing arsenal of cancer immunotherapy treatment options. This study validates the use of intratumoral treatment with synthetic RIG-I agonist ppp-RNA for the therapy of human cancer, with melanoma as potential entry indication amenable to intratumoral treatment. Firstly, we demonstrate that RIG-I expression is closely correlated to cellular and cytokine immune activation in a wide variety of tumor types. Secondly, cellular models of human melanoma confirm susceptibility of cancer cells to ppp-RNA treatment, revealing unexpected heterogeneity between cell lines in their selectivity for RNA features, including sequence, secondary structures and presence of triphosphate. Cellular RNA treatment responses (type I IFN, FasR, MHC-I, cytotoxicity) were demonstrated to be RIG-I dependent using RIG-I KO cells. Thirdly, we show that ppp-RNA treatment of a mouse melanoma tumor model, leads to significant local and systemic anti-tumor effects and survival benefits, associated with a type I IFN response, tumor cell apoptosis and innate and adaptive immune cell activation. For the first time, we demonstrate systemic presence of tumor antigen specific CTLs following treatment with RIG-I agonist. Overall our study demonstrates that ppp-RNA or analogs thereof have the potential to play an important role for cancer treatment in the next wave of immunotherapy. However, potential challenges in the generation and formulation of potent RIG-I agonists remain to be solved.
Citation Format: Mike W. Helms, Eric Parmantier, Kerstin Jahn-Hofmann, Felix Gnerlich, Lars König, Christiane Metz-Weidmann, Monika Braun, Gabriele Dietert, Kaj Grandien, Joachim Theilhaber, Hui Cao, Tim Wagenaar, Max Schnurr, Stefan Endres, Dmitri Wiederschain, Sabine Scheidler, Simon Rothenfusser, Bodo Brunner. Treatment with synthetic RIG-I agonist triphosphate RNA leads to local and systemic anti-tumor effects in a mouse melanoma 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 5024.
Abstract 5031: Regulatory T cell ablation accelerates early stage breast cancer progression
Authors: Du Wei , Martinez Leandro , Robila Valentina , Clark Nicholas , Idowu Michael , Bos Paula , Bos Paula 
Published: August 2019

Abstract
Breast cancer is the most common malignancy in women worldwide. Early detection of pre-invasive breast tumor has dramatically improved due to the routine screening for women. Ductal carcinoma in situ is a non-obligate precursor of breast cancer, and it only progresses to invasive breast cancer in about 40% of patients. We have previously shown that transient ablation of regulatory T (Treg) cells in established breast tumors results in significant reduction of primary and lung metastatic tumor growth. In this study, we aim to investigate the specific role of Treg cells at the pre-malignant stages. Using a spontaneous, stage-wise MMTV-driven polyoma middle T (PyMT) model of murine mammary carcinogenesis, crossed to Foxp3DTR knock-in mice where injection of diphtheria toxin leads to a complete ablation of Treg cells for around 7 days, we found that ablation of Treg cells at the pre-invasive tumor stage resulted in a significant increase in the number of mammary glands developing tumors, as well as tumor growth compared to control mice. Histological examination of tissues revealed that the area of the incipient tumors was larger in Treg cell-ablated mice, and presented a more advanced tumor stage. In addition, Treg cell ablation resulted in a pronounced mammary inflammatory infiltrate, including an increase in tumor-associated macrophages and a soluble cytokine network conducive to tumor progression. Interestingly, Treg cell ablation increased the percentage of cancer stem/progenitor cells in the mammary compartment. Overall, our study demonstrates that unlike their role in established cancers, Treg cells ablation promotes breast cancer progression at early stages.
Citation Format: Wei Du, Leandro Martinez, Valentina Robila, Nicholas Clark, Michael Idowu, Paula Bos, Paula Bos. Regulatory T cell ablation accelerates early stage breast cancer progression [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 5031.