bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3989: Different expression and prognostic effect of PD-L1/PD-1 in SCC and non-SCC of non-small cell lung cancer
Authors: Liu Yunpeng , Wang Shuo , Qu Xiujuan , Liu Zhi , Che Xiaofang , Ling Xu , Hou Kezuo , Fan Yibo , Song Na , Wen Ti , Li Ce 
Published: July 2017

Abstract
Although checkpoint inhibitors targeting PD-1/PD-L1 pathway have demonstrated similar clinical activity in treatment of NSCLC both for squamous(SCC) and non-squamous carcinoma (non-SCC) patients, the predictive role of PD-L1 expression is distinct between two histologies in clinical trials. In order to investigated the expression and prognostic roles of PD-1/PD-L1, data from TCGA and GEO database were analyzed and further validated with our original data by IHC in 133 resected NSCLC tumor tissue(49 SCC and 84 non-SCC). Through the analysis of online data, we concluded that PD-L1 expression in SCC was significantly higher than that of non-SCC. In addition, in non-SCC, PD-L1 was associated with immune response and indicated worse prognosis while no such results were observed in SCC. Further, our original data demonstrated PD-L1 expression in tumor cells(TC) and immune cells(IC) were significantly more often and more intense in SCC(P&lt;0.001). In survival analysis, PD-L1 expression in TC and IC were associated with shorter overall survival in non-SCC (P=0.019 and 0.003, respectively). However, in SCC, PD-L1 did not demonstrate any significant effect neither in TC or IC (P=0.526 and 0.674, respectively) which consistent with online data. Contrary to PD-L1, no significant differences of PD-1 expression in tumor infiltrating lymphocytes(TILs) were showed between two histologies. PD-1 in TILs of SCC correlated with worse prognosis (P=0.025) while in non-SCC there was no correlation(P=0.986). Taken together, these findings suggest distinct regulation mechanisms and clinical significance of PD-L1/PD-1 pathway in NSCLC subgroups.
Citation Format: Yunpeng Liu, Shuo Wang, Xiujuan Qu, Zhi Liu, Xiaofang Che, Xu Ling, Kezuo Hou, Yibo Fan, Na Song, Ti Wen, Ce Li. Different expression and prognostic effect of PD-L1/PD-1 in SCC and non-SCC of non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3989. doi:10.1158/1538-7445.AM2017-3989
Abstract 3991: Profiling the immune tumor microenvironment in primary and recurrent epithelial ovarian cancer
Authors: Ojalvo Laureen S. , Thompson Elizabeth D. , Wang Tian-Li , Meeker Alan K. , Shih Ie-Ming , Fader Amanda N. , Cimino-Mathews Ashley , Emens Leisha A. 
Published: July 2017

Abstract
Clinical trials targeting the immune tumor microenvironment (TME) in epithelial ovarian cancer (EOC) typically have included patients with heavily pre-treated advanced disease and demonstrated only marginal efficacy. A better understanding of how the EOC TME evolves with progression from primary to recurrent disease may inform future immunotherapy trials. Here, we evaluate the immune TME in primary and recurrent EOC using tissue microarrays. Our cohort included matched primary and recurrent tumors from 17 patients, and additional non-matched primary tumors from 20 patients and recurrent tumors from 15 patients. We stained for CD8, FOXP3 (regulatory T cells (Tregs)), CD68 (tumor associated macrophages (TAMs)), programmed cell death protein 1 (PD-1) and programmed death ligand 1 (PD-L1) by immunohistochemistry to interrogate the immune composition of the TME. Tregs increased in recurrent tumors compared to primary tumors (8.0 vs 14.2/HPF, p=0.0210). Higher TAM density was associated with higher levels of Treg and CD8+ T cell infiltrates in recurrent tumors (p=0.001 and p&lt;0.001, respectively), and with higher Treg but not CD8+ T cell infiltrates in primary tumors (p=0.027 and p=0.200). TAM-dense recurrent tumors had increased PD-L1 on tumor cells and immune cells, whereas TAM-dense primary tumors had increased PD-L1 only on immune cells. Increased Tregs in primary tumors correlated with decreased time to first recurrence (17.0 vs 28.5 months, p=0.022). Conversely, increased Tregs in recurrent tumors correlated with longer overall survival (OS) from recurrence (median not met vs 20.0m, p=0.022). Although TAM density did not affect patient survival, analysis of matched primary and recurrent tumors revealed that patients with increased TAMs at recurrence (n=5) had a longer median OS from recurrence than patients without increased TAMs at recurrence (n=12). Tregs increased at recurrence in the majority of matched tumor pairs (n=12), but there was no correlation with survival. In conclusion, the TME of EOC is immunologically active. TAM-dense recurrent disease had higher CD8+ T cell and Treg infiltrates and PD-L1 expression. In this study, patients with increased cellular recruitment to the TME at recurrence had improved survival. Larger, more detailed studies characterizing the evolution of the TME with progression from primary EOC to recurrence are warranted.
Citation Format: Laureen S. Ojalvo, Elizabeth D. Thompson, Tian-Li Wang, Alan K. Meeker, Ie-Ming Shih, Amanda N. Fader, Ashley Cimino-Mathews, Leisha A. Emens. Profiling the immune tumor microenvironment in primary and recurrent epithelial ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3991. doi:10.1158/1538-7445.AM2017-3991
Abstract 3999: Cross talk between tumor cell derived HMGB1 and adaptive B cells in the tumor microenvironment of esophageal squamous cell carcinoma
Authors: Kam Ngar Woon , Guan Xin-Yuan , Kwong Dora Lai-Wan 
Published: July 2017

Abstract
Esophageal squamous cell carcinoma (ESCC) is the most aggressive type of cancer among gastrointestinal cancers. The lack of effective anti-tumor immunity strategy for ESCC patients imposes urgent demand for new treatment paradigm. Tumor microenvironment (TME) is characterized by diverse cell populations (cancerous, immune cells, and pleiotropic nature of cytokines and inhibitory receptors) whose alternations are closely related with tumor progression. High mobility group box chromosomal protein 1 (HMGB1) has been recognized to be expressed in various tumor cells, and importantly it has also been identified as one of the key factors regulating inflammatory reactions.
By comparing differentially expressed genes between ESCC tumors (T) and their corresponding non-tumorous (NT) tissues high-throughput transcriptome sequencing system (RNA-Seq, Illumina HiSeq 2500), we found that the ligands of TIM-3 (an inhibitory receptor), HMGB1 and galectin-9, but not, cell-surface phosphatidylserine, were overexpressed in all ESCC samples when compared to their NT counterparts. We further characterized HMGB1 and galectin-9 gene expression changes in 37 matched primary ESCC T and NT control samples by qRT-PCR. We found that HMGB-1 and galectin-9 mRNA is constitutively expressed in all samples, while ESCC T tissue significantly expressed ~2fold higher of HMGB-1, but not galectin-9, mRNA as compared to paired NT tissue. Histopathological characterization of ESCC tissue by sequential single staining for B-cells (CD20) and plasma cells (CD138), demonstrating that B cell infiltrate was dominated by CD20+ B cells lacking of terminal differentiation into plasma cells. Additionally, CD20+ B cells infiltrates were negative for CD27 (marker for memory B cells) and IgD (marker for naïve B cells). Additionally, we isolated CD20+ B cells from healthy peripheral blood mononuclear cells (PBMC), and stimulated with/without HMGB-1/IgM. Conditional medium (CM) were collected for foci formation and we found that ESCC cell lines KYSE30 and KYSE180 have better capacity for proliferation when culture with activated B cells CM as compared to unstimulated B cells. Collectively, we believe that the suboptimal clinical outcomes relies on CD20+HMGB1 receptor+ B cells that are exposed to high HMGB1 concentrations in the ESCC microenvironment may eventually become pro-tumor B cells subset.
Citation Format: Ngar Woon Kam, Xin-Yuan Guan, Dora Lai-Wan Kwong. Cross talk between tumor cell derived HMGB1 and adaptive B cells in the tumor microenvironment of esophageal squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3999. doi:10.1158/1538-7445.AM2017-3999
Abstract 40: Development of a novel antibody-drug conjugate targeting endosialin/TEM-1: potent antitumor activity in sarcoma
Authors: Sala Gianluca , Iacobelli Stefano , Capone Emily , PIccolo Enza , Sauniere Jean-Fred , Douet Vanessa Vannucci 
Published: July 2017

Abstract
The TEM-1/Endosialin/CD248 receptor is expressed in the cell surface of tumor-associated stroma cells, as well as in sarcoma and neuroblastoma cells. This receptor is emerging as an attractive molecule in diagnostics and therapeutics because of its expression across the stroma of many human tumors, the low to absent expression in normal tissues and accessibility from the vascular circulation. In this study, we present evidence of the preclinical efficacy of a novel Antibody-Drug Conjugate (ADC). It consists of a humanized TEM-1 monoclonal antibody (E.8-3) conjugated to a highly potent payload (TEM-1-ADC). In TEM-1 expressing cancer cell lines, this TEM-1-ADC demonstrated a powerful, specific and target-dependent killing activity. High expression levels of TEM-1 in cells correlated with efficient internalization, efficacy, and cytotoxic effects in vitro. Efficacy studies demonstrated that TEM-1-ADC treatment leads to a long lasting tumor growth inhibition of cell line-based models of human sarcoma. Taken together, our results demonstrated that TEM-1 is an attractive target in sarcoma and suggest that TEM-1-ADC has the potential to be developed into a biotherapeutic agent in these malignancies.
Citation Format: Gianluca Sala, Stefano Iacobelli, Emily Capone, Enza PIccolo, Jean-Fred Sauniere, Vanessa Vannucci Douet. Development of a novel antibody-drug conjugate targeting endosialin/TEM-1: potent antitumor activity in sarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 40. doi:10.1158/1538-7445.AM2017-40
Abstract 4000: Establishing the natural history of the immunosuppressive myeloid microenvironment in an inducible model of lung adenocarcinoma
Authors: Lagraoui Mouna , Dalgard Clifton L. , Sukumar Gauthaman , Huaman Celeste , Summers Thomas , Carter Corey A. , Schaefer Brian C. 
Published: July 2017

Abstract
Tumorigenesis is accompanied by broad changes to the surrounding tissue microenvironment in a tumor- and patient-specific manner. Phenotype shifts in tissue-resident immune cells promote cancer progression by establishing a proliferative inflammatory environment, activating angiogenesis, stimulating tumor cell invasion and suppressing anti-tumor immunity. While the former mechanisms are well appreciated and often targeted by current cancer therapeutics, the nature of the mechanisms controlling establishment of the local immunosuppressive state that contribute to a failure of anti-tumor immunity are less clearly defined. Blockade of tumor antigen-specific T cell killing is clearly a major contributor to the failure to control tumorigenesis. However, evidence suggests that phenotypic shifts in innate immune cell populations also contribute to the failure of anti-tumor immunity. We hypothesize that the emergence of early lung adenocarcinomas is accompanied by a shift in myeloid phenotypes, rapidly establishing a microenvironment favorable to tumor growth, survival and vascularization, and hostile to cell-mediated anti-tumor immune responses. Through the utilization of a Cre-inducible mouse model of p53-null, Kras-G12D+ lung adenocarcinoma, we have begun to define the natural history of the myeloid component of the tumor microenvironment, from tumor initiation to a point equivalent to human stage I adenocarcinoma. Histological, flow cytometry and real-time PCR approaches collectively demonstrate that tumor-associated myeloid phenotypes emerge at a very early stage of disease. These data are consistent with our hypothesis that the myeloid component of the tumor microenvironment plays a crucial role in establishing an immunosuppressive state during early tumorigenesis. Implications of these findings for current and emerging immunotherapies will be discussed.
Citation Format: Mouna Lagraoui, Clifton L. Dalgard, Gauthaman Sukumar, Celeste Huaman, Thomas Summers, Corey A. Carter, Brian C. Schaefer. Establishing the natural history of the immunosuppressive myeloid microenvironment in an inducible model of lung adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4000. doi:10.1158/1538-7445.AM2017-4000
Abstract 4010: Tonggyu-tang, a traditional Korean medicine, suppresses inflammation, potential implications in tumor microenvironment
Authors: Kim Hyoin , Ko Seong-Gyu , Shin Yong Cheol , Kim Ji Hye , Seo Hye-Sook , Kim Tai Young , Hong Se Hyang , Lee Kangwook , Ku Jin Mo , Kim Myeong-Sun , Choi Yu-Jeong , Kang Soo-yeon , Cheon Chunhoo , Ko Youme , Wen Huang Ching , Sasaki Yui , Kang Sohyeon 
Published: July 2017

Abstract
The critical roles of inflammation in the development of cancer have long been appreciated. A growing body of evidence supports the notion that infiltrates of inflammatory cells into tumor microenvironment influence the tumor progression by providing bioactive molecules including pro-inflammatory cytokines. Importantly, the increased number of mast cells within tumor microenvironment has been associated with a poor survival in cancer patients. Moreover, keratinocyte inflammation is known to be crucial for skin tumor development. The use of natural products to reduce inflammation in tumor microenvironment is gaining an interest, because of their reduced toxicity toward normal cells. In this study, we tested the effects of Tonggyu-tang (TGT) which is composed of 14 different herbal extracts on the activity of mast cells. We found that TGT significantly reduced the expression and production of inflammatory cytokines such as IL-4, IL-6, IL-8, and TNF-α in PMA and ionomycin- stimulated HMC-1 (human mast cell line-1). In an attempt to determine molecular mechanism underlying the inhibitory effects of TGT on cytokine expression, we revealed that TGT suppressed MAPK signaling pathway including ERK, p38, and JNK as well as NF-κB pathway, which are known to regulate inflammatory cytokine expression. Similar results were obtained from the LPS-stimulated HaCaT cells, immortalized human keratinocytes. Taken together, our results demonstrate that TGT suppresses inflammation by inhibiting the expression of pro-inflammatory cytokine in both mast cells and keratinocytes, thereby potentially leading to inhibition of tumor progression.
Citation Format: Hyoin Kim, Seong-Gyu Ko, Yong Cheol Shin, Ji Hye Kim, Hye-Sook Seo, Tai Young Kim, Se Hyang Hong, Kangwook Lee, Jin Mo Ku, Myeong-Sun Kim, Yu-Jeong Choi, Soo-yeon Kang, Chunhoo Cheon, Youme Ko, Huang Ching Wen, Yui Sasaki, Sohyeon Kang. Tonggyu-tang, a traditional Korean medicine, suppresses inflammation, potential implications in tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4010. doi:10.1158/1538-7445.AM2017-4010
Abstract 4011: Validation of novel continuous live-cell assays for immune cell activation and killing of blood cell cancers
Authors: Bevan Nicola , Campwala Hinnah , Szybut Clare , Patel Kalpana , Appledorn Dan , Dale Tim , Trezise Derek 
Published: July 2017

Abstract
The blood cancers leukaemia, lymphoma and myeloma are expected to cause the deaths of &gt; 55,000 people in the US in 2016. New immunological approaches afford great promise for improved therapies. Here, we describe novel high throughput live-cell image-based assays for immune cell activation and killing of target cells that are geared toward screening for new treatments for these malignancies. Myeloid and lymphoid cells (Jurkats, Raji, Ramos, WIL2-NS, THP-1, PBMCs) were plated on poly-L-ornithine (PLO) or fibronectin coated 96-well flat plates and monitored over time (h to days) using non-invasive live-cell analysis (IncuCyte). The dynamics of proliferation were quantified via phase-contrast image analysis (% confluence), and validated as a robust measure of cell number by correlating to direct cell counts (Scepter, Millipore) and ATP assays (PerkinElmer). Anti-CD3/IL-2 (0.1-100/10 ng/mL) or anti-CD28 activation (1-100 ng/mL) of PBMCs evoked time-dependent proliferation (0-5d) that was sensitive to the initial cell density and concentration of stimulus. L-Kynurenine (4.69 - 300 µM), a metabolite of the amino acid L-tryptophan caused concentration and time-dependent inhibition of proliferation of PBMCs. To quantify immune-cell killing in co-cultures, WIL2Ns and Ramos B-cell myelomas were first transduced with nuclear-targeted RFP (NucLight Red) to enable direct cell counting. PBMCs, either pre-activated or activated in situ (IL-2/CD3), were then added and the time-course of killing quantified through live (RFP) and dead/apoptotic (annexin-V) cell counting. Together, these protocol developments and validation data illustrate non-invasive continuous measurement of proliferation, activation, clustering and immune-cell killing of non-adherent tumour cells at industrial scale. Unlike flow cytometry, this approach follows the full time-course of the biology without perturbing the cells and allows cell-cell interactions to be visualised. These assays are amenable to testing new therapeutic antibodies, small molecules and genetic T-cell modulation such as CAR-T.
Citation Format: Nicola Bevan, Hinnah Campwala, Clare Szybut, Kalpana Patel, Dan Appledorn, Tim Dale, Derek Trezise. Validation of novel continuous live-cell assays for immune cell activation and killing of blood cell cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4011. doi:10.1158/1538-7445.AM2017-4011
Abstract 4012: Visualization of EPR effect and active targeting by using microscopic mass spectrometry
Authors: Yasunaga Masahiro , Furuta Masaru , Ogata Koretsugu , Fujiwara Yuki , Koga Yoshikatsu , Matsumura Yasuhiro 
Published: July 2017

Abstract
Microscopic mass spectrometry (MMS), in which a microscope is coupled with an atmospheric pressure matrix-assisted laser desorption/ionization (MALDI) and quadruple ion trap time-of-flight (TOF) analyzer has been developed for the investigation of the distribution of various molecules including drugs. The matrix-coated drug sample is ionized and then separated on the basis of its mass-to-charge ratio (m/z). Images were acquired from imaging mass spectrometry (IMS) or tandem mass spectrometry (MS/MS) data. Recently, pharmacokinetic (PK) and pharmacodynamic (PD) studies have become important to evaluate the efficacy and toxicity of the drugs. In these analyses, tissue homogenates are generally used for the quantification by high-performance liquid chromatography (HPLC) or liquid chromatography mass spectrometry (LC-MS). However, they lack the information regarding the drug distribution in a specific anatomical area. The information of the drug distribution would allow us to optimize the drug design enabling more efficient drug delivery. (1) We studied the tissue distribution of paclitaxel (PTX) and its micellar formulation (NK105) using a MMS. NK105 showed much stronger antitumor effects on a human pancreatic cancer BxPC3 xenograft than PTX. In the drug imaging, we demonstrated that NK105 delivered more PTX to the whole tumor tissue. In the mouse model, PTX caused the peripheral neurotoxicity but NK105 did not. Multiple high drug-signal areas surrounding and inside the caudal nerve were observed in the case of PTX, whereas the signals after NK105 administration were quite low. (2) The tissue distribution and controlled drug release of ADC (antibody-drug conjugate) consisting of a tissue factor specific antibody (TF) linked to the anticancer agent monomethyl auristatin E (MMAE) was evaluated in comparison with control-ADC (control antibody-MMAE conjugation). TF-ADC showed stronger antitumor effect on BxPC3 xenograft than control-ADC. We then established the selective detection method of MMAE for distinguishing free MMAE and its conjugated form. The released MMAE signal detected following the accumulation of TF-ADC was greatest 24 h after the administration, compared with the control-ADC at the same time (P&lt;0.01). In summary, we succeeded in visualizing (1) the EPR (Enhanced permeability and retention) effect and (2) active targeting using MMS. The data obtained will facilitate more efficient drug development in the preclinical setting.
Citation Format: Masahiro Yasunaga, Masaru Furuta, Koretsugu Ogata, Yuki Fujiwara, Yoshikatsu Koga, Yasuhiro Matsumura. Visualization of EPR effect and active targeting by using microscopic mass spectrometry [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4012. doi:10.1158/1538-7445.AM2017-4012
Abstract 402: Biomarker-based pooled CRISPR-Cas9 screening: Platform development and validation
Authors: Scales Tim M. , Cross Benedict C. 
Published: July 2017

Abstract
Functional genomic screening with CRISPR-Cas9 has provided a powerful and precise new way to interrogate the phenotypic consequences of gene loss in high-throughput, unbiased analyses. Rapid development of pooled lentivirus and deep-sequencing-led approaches have allowed us and others to exploit this technology in target ID, target validation, drug MOA analysis and patient stratification. Adaptation of the Cas9 nuclease by domain fusion and catalytic inactivation has further provided a novel way to both up and down-regulate gene expression using targeted, high-throughput CRISPRi and CRISPRa tools. To date, the vast majority of screens have been conducted using sgRNA abundance in surviving cell populations as an NGS-based proxy for proliferation, for example for in vitro resistance analysis to a cytotoxic treatment regimen. However, where cellular pathophysiology is uncoupled from cell health, the enormous promise of pooled CRISPR-Cas9 screening has been largely untapped. We now report on the development of a FACS-based platform that can be used to monitor biomarker-based cellular response in combination with high-throughput genetic screening. The endogenous interaction between CD28 and CD80 was used as a proof-of-concept paradigm and the performance of our platform was measured in screen-simulation conditions. We find that FACS-linked NGS was able to robustly identify the CD28 deleted cells from a complex population using a FITC-labelled CD80-Fc. Pseudo-blinding of the data yielded unambiguous identification of the expected target guides, with robust screening metrics, validating a new platform for myriad discovery programmes.
Citation Format: Tim M. Scales, Benedict C. Cross. Biomarker-based pooled CRISPR-Cas9 screening: Platform development and validation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 402. doi:10.1158/1538-7445.AM2017-402