bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5663: Proteomic analysis of exosomes isolated from ccRCC cell lines
Authors: Mizutani Kosuke , Kawakami Kyojiro , Fujita Yasunori , Horie Kengo , Ito Masafumi , Deguchi Takashi 
Published: August 2018

Abstract
Purposes of the study: Clear renal cell carcinoma (ccRCC) is one of the most lethal malignant tumors. Molecular targeted therapies have been used to improve outcomes for metastatic or advanced ccRCC. However, currently approved therapies have limited success and a cure remains elusive. Since ccRCC could be curable if diagnosed at the early stage, novel diagnostic approach is needed to identify circulating markers that may help diagnose early and evaluate prognosis. Exosomes are membrane vesicles with a diameter of 40-150 nm that are secreted by various types of cells including cancer cells. Exosomes contain a variety of molecular constituents of their origin such as proteins and nucleic acids. Over the years, exosome has been suggested to be a novel diagnostic marker. The purpose of this study is to find candidates of ccRCC markers in exosomes. Experimental procedures: Exosomes were collected from cell culture supernatant of RPTEC human renal proximal tubule epithelial cells and ccRCC cell lines (Caki-1, KMRC-1, and OS-RC-2) by ultracentrifugation. Isolation of exosome was confirmed by western blot analysis for CD9. Exosome fraction was analyzed by iTRAQ-based quantitative proteomics. Results: A total of 52 proteins were detected and 3 proteins were found to be upregulated by more than 1.2 fold in exosomes isolated from ccRCC cells compared with those from RPTEC cells. Twelve proteins were found to be downregulated by less than 0.8 fold in exosomes from ccRCC cells compared with those from RPTEC cells. The expression profiles of several proteins were verified by western blot analysis. Conclusions: While major challenges still remain, exosome studies in ccRCC could provide a wealth of information to find novel diagnostic and prognostic markers.
Citation Format: Kosuke Mizutani, Kyojiro Kawakami, Yasunori Fujita, Kengo Horie, Masafumi Ito, Takashi Deguchi. Proteomic analysis of exosomes isolated from ccRCC cell lines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5663.
Abstract 5668: The rational design and evaluation of a peptide inhibitor of the PD-1/PD-L1 interaction
Authors: Boohaker Rebecca J. , Sambandam Vijaya , Suto Mark , Xu Bo 
Published: August 2018

Abstract
Tumor cells exploit immune checkpoints by expressing checkpoint ligands such as PD-L1, effectively masking them from immune destruction. Programmed cell death- 1 (PD-1), plays a major role in tumor immune escape. The interaction of PD-1/PD-L1 inhibits cytotoxic T lymphocyte (CTL) proliferation, induces apoptosis of tumor-specific T cells, and promotes the resistance of tumor cells to CTL attack. Monoclonal antibodies to these proteins have been developed and approved for use in the clinic. Theoretically, peptide mimics, which have the benefit of lower half-life and significantly smaller size, are able to penetrate into solid tumors and tissues better than antibodies, and can function as inhibitors for the PD1/PD-L1 interaction. Here we report for the first time the rational design and validation of a peptide inhibitor to the PD-1/PD-L1 immune checkpoint as a viable alternative to current inhibitory antibodies. We demonstrated, by biolayer interferometry and in silico docking simulations, that a PD-L1 peptide mimetic (PL120131) can interfere with the PD-1/PD-L1 interaction by binding to PD-1. We established the binding constant for the interaction and PL120131 reduces association of PD-L1 in a dose dependent manner. We show that PL120131 is capable of inhibiting PD-1 mediated apoptotic signaling pathway and rescuing Jurkat cells and primary lymphocytes from apoptosis. Additionally, we show that PL120131 treatment allows for CTL anti-tumor activity. Furthermore, PL120131 can maintain co-culture survivability and activity of T Cells in a 3D co-culture model. Together, the characterization of this PD-1/PD-L1 inhibiting peptide provides insight regarding the ability to inhibit PD-L1 binding while maintaining CTL viability and activity. Understanding the mechanism(s) of action of
this peptide has yielded information on the pathways that are drivers of immune evasion in a tumor microenvironment, which may improve and synergize with other forms of immunotherapy, thus increasing efficacy of cancer treatment. Outcomes from this study have provided a path forward to further development of small molecule inhibitors to the PD-1/PD-L1 interaction, and outlines a strategy for the design and development of small molecules to additional cell-surface checkpoint proteins.
Citation Format: Rebecca J. Boohaker, Vijaya Sambandam, Mark Suto, Bo Xu. The rational design and evaluation of a peptide inhibitor of the PD-1/PD-L1 interaction [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5668.
Abstract 5672: Facile generation of single-cell transcriptome and immune repertoire freshly isolated from clinical tumor specimens
Authors: Zhu Junjie , Salahudeen Ameen A. , Giangarra Valeria , Montesclaros Luz , Sapida Jerald , Sharifi Osman , Lee Josephine , Zheng Grace X. , Wagh Dhananjay , Coller John , Sabatti Chiara , Kuo Calvin J. 
Published: August 2018

Abstract
Immunotherapies including cell-based therapies generate deep and durable responses in patients with chemotherapy-refractory cancers. However, in solid tumors, particularly those with stereotypic driver mutations and resultant neoantigens, the clonality and cell states of tumor-infiltrating lymphocytes (TILs) remain poorly understood. Here, we use a droplet-based 5' single-cell RNA-sequencing (scRNA-seq) to simultaneously profile transcriptome and immune repertoire of the same cells, enabling the phenotypic characterization (including cytotoxic and helper T, B, T regulatory and exhausted T cells) of each clonotype. We performed scRNA-seq on unsorted and CD45+-FACS sorted cells from fresh clinical samples of multiple tissue types, including lung, liver and kidney, and obtained on average tens of thousands of cells per sample. We demonstrated that high-quality single-cell suspension can be rapidly and reliably generated from clinical samples. We devised different diversity metrics to appropriately classify the immune repertoire within samples, and cross samples of different tissues. We observed distinct cell type compositions and, more importantly, context-specific T-cell clonal expansion patterns, suggesting the activation of different molecular programs in these tumors. In addition, comparison of non-small cell lung cancer (NSCLC) tumors varying by histology type and patient smoking status showed differences among these phenotypes, suggesting a potential link between immune microenvironments and cancer etiology. In summary, we provide a proof of concept for rapid generation of large number of single-cell transcriptomes of TILs paired with their corresponding TCR cDNA sequence in fresh tumor samples across different tissue types. Further analysis with this methodology on larger clinical cohorts will provide robust correlative prognostic markers of clinical phenotypes of immunotherapy responses. Our analysis strategy of TCR sequences among large clinical cohorts across multiple tumor types will facilitate cell-based therapeutic efforts, including CAR T cell or autologous T cell therapies.
Citation Format: Junjie Zhu, Ameen A. Salahudeen, Valeria Giangarra, Luz Montesclaros, Jerald Sapida, Osman Sharifi, Josephine Lee, Grace X. Zheng, Dhananjay Wagh, John Coller, Chiara Sabatti, Calvin J. Kuo. Facile generation of single-cell transcriptome and immune repertoire freshly isolated from clinical tumor specimens [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5672.
Abstract 5688: Humanized double knock-in mouse models for evaluating in vivo efficacy of the combination therapy of immune-oncology drugs
Authors: Gan Tian , Jin James , Guo Chaoshe , Shen Yuelei , Guo Yanan 
Published: August 2018

Abstract
Over the past years, monoclonal antibodies have been successfully utilized in clinical trials to block or activate key mediators of immune checkpoint pathways, including CTLA-4, PD-1, PD-L1 and OX40 et.al,. Although significant benefits including complete regression and long-term survival were reported among the majority of participants, not all patients respond. In order to optimize the efficacy and minimize toxicities of anticancer immunotherapies, immune checkpoint antibodies are being tested in combination with other conventional therapeutics (radiation, chemotherapy and targeted therapies) and newer immunotherapies (cancer vaccines, oncolytic viruses). However, along the IO drug development process, in vivo efficacy models have always been a rate-limiting step, especially for the combination therapy of two IO antibodies. Therefore, we generated humanized double knock-in mouse to evaluate the in vivo efficacy of combination therapy. For example, humanized double Knock-in B-hPD-1/hOX40 mice pairing with mouse cancer cells, demonstrated a synergistic effect of using hPD-1 and hOX40 antibodies. Additionally, more double knock-in mice targeting immune checkpoint molecules were developed, such as B-hPD-1/hPD-L1, B-hPD-1/hCTLA-4, B-hPD-1/hLAG3, B-hPD-1/hTIM3, B-hPD-1/hTIGIT, B-hPD-1/hBTLA, et al,. Humanized double knock-in mice, represent useful in vivo efficacy models for evaluation of the combination effects of various IO drugs.
Citation Format: Tian Gan, James Jin, Chaoshe Guo, Yuelei Shen, Yanan Guo. Humanized double knock-in mouse models for evaluating in vivo efficacy of the combination therapy of immune-oncology drugs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5688.
Abstract 5694: Evaluation of the in vivo efficacy of immune-oncology drugs targeting stimulatory immune checkpoint molecules using humanized knock-in mice
Authors: Xia Tongmei , Guo Chaoshe , Shen Yuelei , Guo Yanan 
Published: August 2018

Abstract
Cancer immunotherapy is one of the most promising research areas in the field of cancer therapy. Many pharmaceutical and biotech companies in the world are devoting great effort to develop cancer immunity-related treatment antibodies. However, along the IO drug development process, in vivo efficacy models have always been a rate-limiting step. In most cases, a human monoclonal antibody does not have mouse cross-reactivity. Mouse surrogate antibodies were often used in immune-competent syngeneic mouse models to evaluate in vivo efficacy of IO drugs. However, the efficacy of a surrogate antibody cannot fully represent the human drug in the clinical scenario. Therefore, we generated humanized knock-in mice to evaluate the in vivo efficacy of human IO antibodies. For example, human OX40 knock-in (B-hOX40) mice were generated with a chimeric OX40 receptor, which is recognizable by stimulatory human OX40 antibodies. Additionally, more knock-in mice targeting stimulatory immune checkpoint molecules were developed and validated, such as B-hCD137, B-hGITR, B-hCD27, B-hCD40, B-hCD28, B-hCD3 et al,. All these mouse models response well to the corresponding human IO antibodies, proving that they are powerful tools for in vivo efficacy evaluation of human stimulatory immune checkpoint antibodies.
Citation Format: Tongmei Xia, Chaoshe Guo, Yuelei Shen, Yanan Guo. Evaluation of the in vivo efficacy of immune-oncology drugs targeting stimulatory immune checkpoint molecules using humanized knock-in mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5694.
Abstract 5695: Use of certain antihistamines among breast cancer patients confers survival benefit
Authors: Olsson Hakan L. 
Published: August 2018

Abstract
H1-antihistamines have not been widely studied in relation to cancer therapy, despite being among the most common medications used globally, and having become increasingly sophisticated, cheap and safe.
In a nation-wide study of the entire Swedish population using the Drug Prescription Registry, Cancer Registry and Cause of Death Registry- the first of its kind - we investigated the effects of the six major antihistamines (cetirizine, clemastine, desloratadine, ebastine, fexofenadine and loratadine) on breast cancer-related (as well as all-cause) mortality. Our study includes 61,627 Swedish women with breast cancer diagnosed between July 1st 2005 and December 31st 2013. 14,711 used at least one of the six major antihistamines. Both peri- and post-diagnostic antihistamine use was analyzed, as well as the use among different subgroups of patients, divided according to age, stage and estrogen receptor status, was analyzed.
Here, we show a consistently beneficial effect of desloratadine and ebastine use on breast cancer survival (in the peri-diagnostic analysis, for desloratadine, HR=0.79 [95% CI 0.63-0.99], P=0.044; and for ebastine users, HR=0.57 [95% CI 0.32-1.03], P=0.064; relative to non-users) and a consistently negative effect on breast cancer survival of clemastine use (in the peri-diagnostic analysis, HR=1.24 [95% CI 1.05-1.47], P=0.013; relative to non-users). Loratadine use is associated with better survival in the peri-diagnostic analysis (HR=0.78 [95% CI 0.63-0.97], P=0.022) relative to non-use. No significant effects were seen for cetirizine use or fexofenadine use. Post diagnostic use. A woman with breast cancer using desloratadine will lower her relative risk of breast cancer-related death with 15% after one
year's use and 17% after two years' use (both risks relative to a woman of the same age and the same tumor status).
Conclusion. Use of desloratadine and ebastine may may significantly improve survival in breast cancer with few side effects.
Citation Format: Hakan L. Olsson. Use of certain antihistamines among breast cancer patients confers survival benefit [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5695.
Abstract 5724: Homologous recombination repair gene mutations for DNA repair and immune oncology drug combinations
Authors: Dry Jonathan R. , Lai Zhongwu , Dougherty Brian , Barrett Carl , Criscione Steven 
Published: August 2018

Abstract
Exciting clinical benefit has been seen from both immune checkpoint inhibitors and PARP inhibitors in several cancer types. Initial reports have suggested the tumor mutational burden (TMB) may be a tumor agnostic marker for predicting immunotherapy (IO) response. Deficiencies in DNA damage repair (DDR) resulting from BRCA1 and BRCA2 mutations can lead to an accumulation of tumor mutations, and sensitivity to PARP inhibitors. We hypothesized that patients with germline or somatic mutations in BRCA1/2 or other homologous recombination repair (HRR) genes, termed “HRRm”, will have higher TMB, higher immune infiltration and activity, and greater benefit from the combination of DDR and IO therapies. We investigated the relationship between DDR deficiencies, TMB, PDL1, transcriptomic immunoscores and drug response across The Cancer Genome Atlas (TCGA) disease cohorts, data from AstraZeneca's clinical studies and a linked NSCLC genomic and EHR dataset from Foundation Medicine and FlatIron Health. HRRm cancer samples show higher TMB in several cancer types. This does trend with higher PDL1 but does not associate with transcriptomic immunoscores. HRRm could be a practical clinical biomarker to select patients with DDR defects likely to benefit from combination of DDR and IO therapies.
Citation Format: Jonathan R. Dry, Zhongwu Lai, Brian Dougherty, Carl Barrett, Steven Criscione. Homologous recombination repair gene mutations for DNA repair and immune oncology drug combinations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5724.
Abstract 5728: DNA demethylating agents and interferons as modulators of Wnt/β-catenin signaling in colorectal cancer
Authors: Ettayebi Ilias , Mehdipour Parinaz , Singhania Rajat , Chakravarthy Ankur , Medina Tiago , Shen Shu Yi , Ishak Charles , Roulois David , Carvalho Daniel De 
Published: August 2018

Abstract
p.p1 {margin: 0.0px 0.0px 0.0px 0.0px; font: 12.0px 'Times New Roman'} Colorectal cancer (CRC) is the second leading cause of death from cancer in men and the third in women in Canada. There is accumulating evidence suggesting that CRC is organized in a hierarchical manner, at the apex of which are the Cancer-Initiating Cells (CIC). Furthermore, results from xenograft models and human clinical trials indicate a selective enrichment of CICs in tumours that are resistant to therapy, suggesting that targeting CICs may represent a new paradigm in cancer treatment. We have previously reported the treatment with low dose of the DNA demethylating agent, 5-Aza-2'-deoxycytidine (5-AZA-CdR), can target CICs through the activation of the RIG1-MDA5 viral sensing sensing pathway, leading to an anti-viral response in cancer cells. Although it is now known that 5-AZA-CdR induces a state of “viral mimicry” in these cancer cells, the mechanism by which 5-AZA-CdR can specifically target CICs is not well understood. In this study, we propose a novel intersection between RIG1-MDA5-IRF7 and Wnt/β-catenin pathways. We found that treatment of CIC enriched cancer cells with both 5-AZA-CdR and type I and III interferons reduced canonical Wnt/β-catenin signalling. Furthermore, treatment with type I and III interferons showed a reduced CIC frequency in colorectal cancer cells in vitro. Mechanistically, we found that IRF7 and β-catenin interact in the nucleus, giving rise to a novel, non-canonical pathway that can modulate WNT signalling. These findings may explain a novel pathway by which 5-AZA-CdR can specifically target CIC enriched populations in colorectal cancer, and highlights the importance of innate immune pathways in epigenetic therapy.
Citation Format: Ilias Ettayebi, Parinaz Mehdipour, Rajat Singhania, Ankur Chakravarthy, Tiago Medina, Shu Yi Shen, Charles Ishak, David Roulois, Daniel De Carvalho. DNA demethylating agents and interferons as modulators of Wnt/β-catenin signaling in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5728.
Abstract 5746: CRISPR9-mediated FGL2-KO in tumor cells impairs tumor progression in brain and triggers antitumor immune memory systematically via NF-κB dependent Batf3 expression in DCs
Authors: Yan Jun , Zhao Qingnan , Gabrusiewicz Konrad , Kong Ling-Yuan , Huo Longfei , Xia Xueqing , Wei Jun , Xu Jingda , Davis Eric , Heimberger Amy B. , Li Shulin 
Published: August 2018

Abstract
Brain cancer is the 10th leading cause of death in United States with increasing primary tumor morbidity and secondary brain metastasis morbidity. Glioblastoma (GBM) is most lethal brain tumor with less than 5% 5 years survival rate marked by significant resistance to majority of therapies targeting tumor cells or tumor microenvironment. Here we shown one approach to convert aggressive GBM cells to immunogenic tumor cells by knockout FGL2 in GBM cells to evoke efficient anti-tumor immunosurvilliance. FGL2 is an immunosuppressive molecule and its expression level is strongly correlated with glioma grade and poor diagnosis. FGL2 from GBM cells, but not from host cells, is essential for immune evasion dependent GBM progression using both preclinical GBM and brain metastatic tumor models. Knockout FGL2 in GBM cells completely abolish tumor progression of GBM models challenged with low or high number of tumor cells in immunocompetent mice and protect mice from tumor rechallenge in periphery. This eradication effect is impaired in immune deficient mice and CD8+ T cells depleted mice, but not in FGL2KO mice, showing the necessarily of immune system to eliminate FGL2KO tumor cells and the requirement of FGL2 in tumor cells to evade immunosurvilliance. To understand how the systemic CD8+ T cell-dependent anti-tumor response and memory was induced by FGL2KO GBM cells, we studied the impact of FGL2KO tumor cells on dendritic cells (DCs) which control immune response via its critical role in the generation of effective cytotoxic T lymphocyte (CTL) responses. Knockout FGL2 in GBM cells induced CD8a+/CD103+ DCs accumulation in brain in vivo; DCs proliferation and CD103+ DCs induction in vitro. In agreement with this discovery, knockout Batf3, a key transcription factor regulating CD8a+/CD103+ DCs, reverse the impact of FGL2KO in GBM cell in vivo. By molecule analysis, a novel signaling pathway was revealed that knockout FGL2 in GBM cells induce NF-κ B activation, and this activation induced Batf3 and associated CD103 expression in DCs. Therefore, target specific molecule in GBM cells, such as knockout FGL2, can convert aggressive GBM cells to immunogenic cells, pointing to new approach for immune therapy.
Citation Format: Jun Yan, Qingnan Zhao, Konrad Gabrusiewicz, Ling-Yuan Kong, Longfei Huo, Xueqing Xia, Jun Wei, Jingda Xu, Eric Davis, Amy B. Heimberger, Shulin Li. CRISPR9-mediated FGL2-KO in tumor cells impairs tumor progression in brain and triggers antitumor immune memory systematically via NF-κB dependent Batf3 expression in DCs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5746.