bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B46: The long noncoding RNA INCA1 is a novel regulator of PD-L1 expression in tumors
Authors: Mineo Marco , Lyons Shawn M. , Ferrer-Luna Ruben , Ito Hirotaka , von Spreckelsen Niklas , Alayo Quazim A. , Khalsa Jasneet K. , Shah Khalid , Ligon Keith L. , Beroukhim Rameen , Ivanov Pavel , Anderson Paul J. , Nakashima Hiroshi , Lawler Sean E. , Chiocca E. Antonio 
Published: March 2020

Abstract
Long noncoding RNAs (lncRNAs) are key regulators of gene expression both in physiologic and pathologic conditions. Although the role of lncRNAs in tumorigenesis is now emerging, their function in cancer-mediated immunosuppression remains unexplored. We have identified the interferon-γ (IFNγ)-stimulated noncoding RNA 1 (INCA1) as a novel lncRNA expressed from the PD-L1 locus and showed that INCA1 is a key regulator of PD-L1 expression. Silencing INCA1 decreased PD-L1 expression both at basal level and in response to IFNγ stimulation in multiple tumor types. INCA1 knockdown sensitized tumor cells to cytotoxic T cell-mediated killing. Moreover, tumors with silenced INCA1 showed increased CAR T trafficking and activity in vivo. These findings provide novel insights into the biology of PD-L1 regulation and tumor immune evasion. INCA1 is thus a new target for cancer immunotherapy.
Citation Format: Marco Mineo, Shawn M. Lyons, Ruben Ferrer-Luna, Hirotaka Ito, Niklas von Spreckelsen, Quazim A. Alayo, Jasneet K. Khalsa, Khalid Shah, Keith L. Ligon, Rameen Beroukhim, Pavel Ivanov, Paul J. Anderson, Hiroshi Nakashima, Sean E. Lawler, E. Antonio Chiocca. The long noncoding RNA INCA1 is a novel regulator of PD-L1 expression in tumors [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr B46.
Abstract B63: Calcium electroporation offers an effective local treatment with immunogenic cell death and the potential for systemic remission in melanoma
Authors: Tremble Liam Friel , Heffron Cynthia , Forde Patrick 
Published: March 2020

Abstract
Electrochemotherapy is an established treatment modality in which chemotherapeutics are delivered systemically or locally in combination with local electrical pulses. Pulsing parameters are optimized to induce the reversible formation of pores in the cell membrane, leaving cells intact and healthy. Osmotic gradients during poration result in the rapid uptake of extracellular components, which results in enhanced chemotherapeutic uptake, between 5 to 2,000-fold depending on the hydrophobicity of the drug used. Complete local response rates for dermal lesions exceed 80%. Treatment is suitable for use in proximity to vasculature and offers superior cosmetic results in comparison to surgery when used in areas such as the eyelid or mouth. Recent advances have, however, been able to replace cytotoxic chemotherapeutic agents with calcium with no decrease in efficacy. The nature of cell death induced is believed to be acute, but to date has not been clearly characterized. Using Flou-4 to track the duration of elevated intracellular calcium concentrations, we have shown that elevated calcium levels persist for hours following treatment. Cell death occurs in 60-80% of cells treated in vitro within 8 hours of treatment. Cells surviving this initial insult show no detectable loss in survival or growth potential and appear otherwise unaffected. Necrotic cell death provides a significant source of damage-associated molecular patterns and may aid the generation of anticancer immune responses. Using cocultured macrophages, we have been able to show that treatment can indirectly boost cytotoxic T-cell responses via tumor-associated macrophages. The elucidation of cell death during treatment is critical for the effective optimization of clinical treatment parameters, which has hitherto been determined empirically. Other advances, such as the use of high-frequency electroporation, are transforming the clinical delivery. It is foreseeable that the requirement of surgical theaters may be avoided with the development of a pain-free treatment in the absence of cytotoxic drugs.
Note:This abstract was not presented at the conference.
Citation Format: Liam Friel Tremble, Cynthia Heffron, Patrick Forde. Calcium electroporation offers an effective local treatment with immunogenic cell death and the potential for systemic remission in melanoma [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr B63.
Abstract B68: NF-kB p50-deficient immature myeloid cell (p50-IMC) adoptive transfer slows the growth of murine prostate and pancreatic ductal carcinoma
Authors: Suresh Rahul R. , Barakat David J. , Barberi Theresa , Zheng Lei , Jaffee Elizabeth M. , Pienta Kenneth J. , Friedman Alan D. 
Published: March 2020

Abstract
Macrophages and dendritic cells lacking NF-kB p50 having an increased proinflammatory phenotype. Melanoma, fibrosarcoma, colon carcinoma, and glioblastoma grow slower in p50-/- mice, with tumor-associated macrophage M2-to-M1 reprogramming. We therefore evaluated the efficacy of NF-kB-deficient immature myeloid cell (p50-IMC) adoptive transfer. Immature myeloid cells (IMCs) were utilized to favor tumor and lymph node localization. WT-IMC or p50-IMC were generated by culturing lineage-negative marrow cells from WT or p50-/- mice in media containing TPO, SCF, and FL for six days followed by M-CSF for one day. Mice inoculated with Hi-Myc prostate cancer (PCa) or K-RasG12D pancreatic ductal carcinoma (PDC) transfected with luciferase received three doses of 1E7 IMCs every 3-4 days. IMC infusions were preceded by a single dose of 5-fluorouracil (5FU) to reduce marrow production of myeloid cells, to reduce tumor myeloid cell numbers, and to potentially release tumor neoantigens. PCa grew slower in p50-/- mice, and absence of host p50 led to prolonged survival of mice inoculated orthotopically with PDC. 5FU followed by p50-IMC slowed PCa or PDC tumor growth ~3-fold in contrast to 5FU followed by WT-IMC, 5FU alone, or p50-IMC alone. Slowed tumor growth was evident for 12 of 14 PCa tumors but only 8 of 15 PDC tumors, leading us to focus on PCa for additional analyses. p50-IMC predominantly generated PCa and draining lymph node F4/80+ macrophages, but also CD11b+F4/80-CD11c+ conventional dendritic cells, with tumor and nodal macrophages having increased Ly6C and MHCII and reduced MR compared to host macrophages, indicative of a proinflammatory phenotype. p50-IMC also led to 5-fold increased activated tumor CD8 T cells, and antibody-mediated CD8 T-cell depletion obviated slower tumor growth induced by 5FU followed by p50-IMC. Adoptive transfer of patient-derived NF-kB p50-deficient p50-IMC, potentially generated by expansion and gene editing of marrow CD34+ cells, may contribute to the therapy of these and additional cancers.
Citation Format: Rahul R. Suresh, David J. Barakat, Theresa Barberi, Lei Zheng, Elizabeth M. Jaffee, Kenneth J. Pienta, Alan D. Friedman. NF-kB p50-deficient immature myeloid cell (p50-IMC) adoptive transfer slows the growth of murine prostate and pancreatic ductal carcinoma [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr B68.
Abstract B73: A novel candidate for immunologic target in treatment of multiple myeloma
Authors: Matsushita Maiko , Saito Saku , Mori Kanae , Yokoe Shinya , Ichikawa Daiju , Hattori Yutaka 
Published: March 2020

Abstract
Background: Despite the development of novel drugs, including immune modulatory drugs (IMiDs) and proteasome inhibitors, multiple myeloma is still an uncurable disease. In particular, patients with high-risk chromosomal abnormalities, such as t (4;14) or del17, have poor prognosis. Recently, antibodies or CAR-T cells have been shown to be effective, suggesting that myeloma cells are sensitive to immune reactions. We have previously identified an HLA-A*24:02-restiricted epitope from a novel cancer-testis antigen CXorf48. In this study, we aim to characterize cytotoxic T lymphocyte (CTL) against this antigen and investigate the possibility of the CTLs for adoptive T-cell therapy in myeloma treatments.
Methods: Expression of CXorf48 gene was examined by RT-PCR of myeloma cell lines. We then treated myeloma cells with low CXorf48 expressions by demethylating agents, 5-azacytidine (5-aza) or 5-aza-2’-deoxycytidine (DAC), and checked the expression level of this gene by quantitative RT-PCR. Furthermore, CXorf48-specific CTLs were induced from peripheral blood mononuclear cells of HLA-A*24:02-positive healthy donors and their antigen recognition was examined by ELISpot assay and 51Cr cytotoxicity assay. We also analyzed T-cell receptor (TCR) repertoire using dextramer-sorted CTLs and transduced the TCR genes into Jurkat cells.
Results: Expression of CXorf48 gene was found in most myeloma cell lines including those with t (4;14) or del17. In addition, the gene expression was significantly increased by DAC in CXorf48-low myeloma cells, which caused enhanced recognition by anti-CXorf48 CTLs. We also identified CXorf48-specidfic TCR genes of CTLs from two donors, and generated TCR gene-transduced T cells.
Conclusions: CXorf48 might be a useful target for immunotherapy in combination with demethylating agents for high-risk myeloma. Aiming at CXorf48-specific adoptive therapy, we are analyzing CXorf48-specific TCR-transduced human T cells.
Citation Format: Maiko Matsushita, Saku Saito, Kanae Mori, Shinya Yokoe, Daiju Ichikawa, Yutaka Hattori. A novel candidate for immunologic target in treatment of multiple myeloma [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr B73.
Abstract B8: Multiplex quantification of immunomodulatory proteins in tissue and plasma using next-gen targeted MRM mass spectrometry
Authors: Whiteaker Jeffrey R. , Zhao Lei , Ivey Richard G. , Voytovich Julia , Schoenherr Regine M. , Huang Dongqing , Kennedy Jacob J. , Paulovich Amanda G. 
Published: March 2020

Abstract
Quantifying the many immunomodulatory proteins in the “cancer-immunity cycle” is critical for both patient selection and development of novel immunotherapies. Conventional technologies to measure proteins (IHC, ELISA, Western blot, flow cytometry) are often semiquantitative, not multiplexable, feature poor specificity, and are difficult to develop. Due to these limitations, investigators have turned to mRNA-based measurements to infer protein expression of immunomodulatory factors. However, as has been unequivocally demonstrated for human breast, colorectal, and ovarian cancers (Pubmed IDs: 27251275, 25043054, 27372738), RNA levels can be poor predictors of protein levels or activity. Thus, direct quantification of proteins is desirable. As part of the National Cancer Institute’s Cancer Moonshot, we are developing &gt;300 multiplex assays for quantifying immunomodulatory proteins in tissue and plasma using a next-gen technology for protein quantification, based on targeted multiple reaction monitoring mass spectrometry (MRM-MS). MRM-MS complements traditional immunoassays by enabling highly specific, precise, harmonizable quantification of proteins in biospecimens, even at high multiplex levels. As proof of concept, we will present a novel multiplex assay based on next-gen MRM-MS for quantification of 47 immunomodulatory proteins in plasma and/or tumor tissue. The technology uses immunoaffinity enrichment coupled with MRM-MS (immuno-MRM assay). Assay bioanalytical validation was conducted in accordance with industry standards for use in FFPE tissue and plasma matrices and included determination of limits of detection, linear range of response, intraday and interday repeatability, stability of analytes in sample processing, and characterization of reproducibility of endogenous analyte measurement. The mean linear range was over three orders of magnitude with median intra- and interday CVs less than 10%. The characterized assays are being applied to a panel of tumor specimens from a variety of cancer types to document detection and determine minimum sample requirements. Additional assay panels are under development to provide measurements of up to 350 immunomodulatory proteins.
Citation Format: Jeffrey R. Whiteaker, Lei Zhao, Richard G. Ivey, Julia Voytovich, Regine M. Schoenherr, Dongqing Huang, Jacob J. Kennedy, Amanda G. Paulovich. Multiplex quantification of immunomodulatory proteins in tissue and plasma using next-gen targeted MRM mass spectrometry [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr B8.
Abstract B81: Prognostic significance of matrix metalloproteinase-3 expression in patients with resected lung adenocarcinoma
Authors: Hung Jung-Jyh , Hsu Wen-Hu 
Published: March 2020

Abstract
Background: Epithelial-mesenchymal transition (EMT) is one of the major molecular mechanisms inducing tumor invasion and metastasis. Many EMT regulators, such as Snail, TWIST1, and Slug, induce EMT through inhibiting E-cadherin. The process of EMT generates cells with stem-like properties. Bmi1, Oct4, and Nanog are molecules related to cancer stem cell (CSC) properties. The expression of matrix metalloproteinase-3 (MMP-3) in lung tissue leads to activation of Rac1b, and activation of EMT by Rac1b/MMP-3 pathway stimulates bypass of oncogene-induced senescence and progression to lung adenocarcinoma. However, the prognostic significance of MMP-3 expression in patients of lung cancer remains unknown.
Methods: The clinicopathologic characteristics of 92 patients with lung adenocarcinoma at Taipei Veterans General Hospital were retrospectively reviewed. Expression of MMP-3 was investigated using immunohistochemistry. Their prognostic significance in probability of overall survival was analyzed.
Results: With a median follow-up time of 27.7 months (27.4 ± 9.3), the 2-year probability of overall survival rate was 77.3%. By immunohistochemistry, overexpression of MMP-3 was identified in 12 (13.0%) of the 92 patients. Univariate analysis showed that MMP-3 overexpression was a significant prognostic factor for worse probability of overall survival (P = 0.019). Order age was also a significant prognostic factor for worse probability of overall survival (P = 0.027). Multivariate analysis showed that order age (P = 0.027) and MMP-3 overexpression (P = 0.015) were both significant prognostic factors for worse probability of overall survival.
Conclusions: Our study showed that order age and MMP-3 overexpression were both significant prognostic factors for worse probability of overall survival in resected lung adenocarcinoma.
Citation Format: Jung-Jyh Hung, Wen-Hu Hsu. Prognostic significance of matrix metalloproteinase-3 expression in patients with resected lung adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr B81.
Abstract B83: A role of a transcription factor TOX in promoting CD8+ T-cell exhaustion in cancer via single-cell transcriptome analysis
Authors: Kim Kyungsoo , Park Seyeon , Ha Sang-Jun , Lee Insuk 
Published: March 2020

Abstract
Recently to treat cancer, several cancer therapies have been developed such as chemotherapy, radiation therapy, immunotherapy, targeted therapy, and hormone therapy. Among several cancer therapies, immunotherapies have recently been developed and shown clinical impacts on a significant number of patients. However, even in the case of immunotherapy, every cancer therapy does not have a 100% response rate. Since the difference in the response rate is mainly due to tumor microenvironment, we need to understand the tumor microenvironment to overcome the low response rate of therapies. Previously, tumor microenvironment was analyzed using cell sorting techniques such as FACS, but it is hard to observe every cell subtype. However, recently, a new technique called single-cell RNA sequencing has been developed. Single-cell RNA sequencing sequences RNAs from every single cell from the sample. Using single-cell RNA sequencing, we can get transcriptome information from whole tumor sample. Therefore, we can observe interactions between the immune cells and the tumors cells using single-cell RNA sequencing. First of all, to focus on the microenvironment of tumor tissue, we analyzed public single-cell RNA sequencing data and unraveled the phenotype of exhausted T cells. By analyzing single-cell RNA sequencing data from the public, we found TOX, a T cell exhaustion-associated transcriptional regulator important for maintaining exhausted T cell. We confirmed that TOX is expressed in the context of exhausted T cell by FACS analysis. Also, using trajectory analysis, we observed expression pattern of TOX through T-cell exhaustion process. Additionally, we analyzed TCGA data to observe the effect of TOX on survival rate. Through analyzing several data such as expression data, binding assay, and open chromatin region of exhausted T cells, we found a potential role of the TOX gene. We also confirmed that the TOX gene can regulate the expression of other checkpoint molecules by knockdown experiment. Here, we found a novel regulator in the tumor microenvironment using single-cell transcriptomics.
Citation Format: Kyungsoo Kim, Seyeon Park, Sang-Jun Ha, Insuk Lee. A role of a transcription factor TOX in promoting CD8+ T-cell exhaustion in cancer via single-cell transcriptome analysis [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr B83.
Abstract B9: Screening the membrane proteome to determine antibody specificity and discover new immunomodulatory targets
Authors: Sullivan Tabb , Huston-Paterson Duncan , Azuelos Charles , Wilf Rona , Doranz Benjamin 
Published: March 2020

Abstract
Integral Molecular specializes in characterizing monoclonal antibodies (MAbs) against structurally complex targets, including GPCRs, ion channels, and immuno-oncology (I-O) targets. The Membrane Proteome Array (MPA) enables off-target analysis by screening antibodies against an expression array of &gt;5,300 human membrane proteins. Each membrane protein is presented in live cells in its structurally intact and native conformation with appropriate post-translational modifications. Binding interactions are tested and validated by high-throughput flow cytometry, providing comprehensive assessment of off-target antibody interactions. Membrane proteins in the MPA are fully functional and can be used for phenotypic screening to identify new therapeutic targets, as demonstrated by our recent discovery of novel costimulatory molecules against cytotoxic T lymphocytes (CTLs).
Citation Format: Tabb Sullivan, Duncan Huston-Paterson, Charles Azuelos, Rona Wilf, Benjamin Doranz. Screening the membrane proteome to determine antibody specificity and discover new immunomodulatory targets [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr B9.
Abstract B91: BRCA1 mutation in breast cancer cells and generation of metastasis associated fibroblasts
Authors: Latha Neetha Rajan , Varghese Geetu Rose , Jaikumar Vishnu Sunil , Rajan Arathi , Nadhan Revathy , Warrier Arathy , Srinivas Priya 
Published: March 2020

Abstract
Tumor microenvironment plays an indispensable role in cancer development as it can be described as the territory where the interaction takes place between tumor and microenvironment elements such as the endothelial cells, epithelial cells, fibroblasts, immune cells, and ECM proteins. Among these structural stromal components, specifically cancer-associated fibroblasts (CAFs) have attracted substantial attention over recent decades. CAFs in the tumor microenvironment assist the accelerated growth demands of the cancer cells and enhance cancer progression through their paracrine activity by the enhanced secretion of growth factors and cytokines, which also help in remodeling the extracellular matrix (ECM). Studies reveal that CAFs have extended their role in cancer metastasis by accompanying the cancer cells to distant metastatic sites. From our in vitro studies, we have identified that coculturing the CAFs with the conditioned medium (CM) from BRCA1 mutated but not wild-type cancer cells results in the transformation of CAFs to an altered phenotype. Since these transformed CAFs showed increased migrative, invasive, and proliferative abilities, we named them “Metastasis Associated Fibroblasts” (MAF) (Sreelatha et al., 2018). The MAF thus generated showed a significant increase in the expression of the Ezrin, Radixin, and Moesin (ERM) protein complex, which may be attributed to the association of BRCA1 C-terminal (BRCT) domains of BRCA1 with the ERM protein superfamily. This association of BRCA1 with the key regulators of ERM complex can influence cell adhesion and motility, suggesting that BRCA1 may act upon their signaling pathways. To study the effect of BRCA1 mutation and ERM protein expression in CAFs in vivo, BRCA1 mutated breast cancer cells were orthotopically implanted to NOD-SCID mice. CAFs isolated from the tumor were analyzed for the expression of ERM. It was found that there is a significant increase in the expression of ERM protein in the tumors isolated from mice that were implanted with BRCA1 mutated breast cancer cells compared to the mouse group that received BRCA1 wild-type breast cancer cells. Inhibitors to ezrin and CCL5 could effectively reduce the metastatic potential of BRCA1 mutant cancer models. A combination of ezrin inhibitor (NSC 668394) and plumbagin, a plant-derived naphthoquinone that effectively reduces BRCA1 mutant breast cancer cell proliferation, is under investigation.
Citation Format: Neetha Rajan Latha, Geetu Rose Varghese, Vishnu Sunil Jaikumar, Arathi Rajan, Revathy Nadhan, Arathy Warrier, Priya Srinivas. BRCA1 mutation in breast cancer cells and generation of metastasis associated fibroblasts [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr B91.