bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2963: CDX-585, a novel bispecific antibody targeting PD-1 and ILT4
Authors: Thomas Lawrence J. , Vitale Laura A. , Murphy Michael , Xia Collin , Peng Zeyu , Ejas Asma , Patel Montu , Boyer James , Baronas April R. , O'Neill Thomas , Widger Jenifer , Mills-Chen Laura , Crocker Andrea , Ma Mark , Chen Mingjiu , Davis Hugh M. , Hammond Russ A. , Taglienti Cherie , Yellin Michael , Goldstein Joel , Alvarado Diego , Marsh Henry C. , Keler Tibor 
Published: April 2023

Abstract
Both PD-1 and ILT4 (LILRB2, CD85d) have well established immunosuppressive effects that enable tumors to evade anti-tumor immunity. Tumor expression of PD-L1 and ILT4 has been associated with poor clinical outcomes in several cancer types. Recently, ILT4 activation has been postulated as a resistance mechanism for PD-1/PD-L1 blockade prompting the investigation of dual blockade of these pathways. Siu, L.L. et al. (2022 Clin Cancer Res 28: 57-70) reported encouraging results of the initial clinical study combining the ILT4 antagonist mAb MK-4830 with pembrolizumab. The combination was generally well tolerated and led to several durable responses including in PD-1/PD-L1 refractory patients. We have combined novel PD-1 (mAb E1A9) and ILT4 (mAb 7B1) antagonist antibodies into a tetravalent IgG-scFv format bispecific antibody (bsAb, CDX-585). CDX-585 was engineered to avoid effector functionality by eliminating interaction with Fcγ receptors, and to increase its half-life by enhancing binding to FcRn. As expected, CDX-585 inhibits interaction of PD-1 and ILT4 with their ligands, results in potent inhibition of PD-1 signaling and enhances myeloid cell inflammatory responses to stimulation through toll like receptors (LPS) or CD40 (CD40 agonist mAb). In mixed lymphocyte reactions CDX-585 promoted greater T cell activation than the combination of the parental mAbs. Similarly, CDX-585 demonstrated superior anti-tumor activity over the combination of the parental mAbs in a humanized mouse model of melanoma. CDX-585 has completed GMP manufacturing and IND-enabling activities. Doses of CDX-585 up to 60 mg/kg were well tolerated in cynomolgus macaques and displayed a favorable pharmacokinetic profile. Together these data demonstrate that CDX-585 effectively combines PD-1 and ILT4 blockade into one molecule with favorable biophysical and functional characteristics supporting the initiation of a dose-escalation clinical trial in patients with advanced solid tumors.
Citation Format: Lawrence J. Thomas, Laura A. Vitale, Michael Murphy, Collin Xia, Zeyu Peng, Asma Ejas, Montu Patel, James Boyer, April R. Baronas, Thomas O'Neill, Jenifer Widger, Laura Mills-Chen, Andrea Crocker, Mark Ma, Mingjiu Chen, Hugh M. Davis, Russ A. Hammond, Cherie Taglienti, Michael Yellin, Joel Goldstein, Diego Alvarado, Henry C. Marsh, Tibor Keler. CDX-585, a novel bispecific antibody targeting PD-1 and ILT4 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2963.
Abstract 3277: In vivo CRISPR screening identifies PTDSS1 as a potential combinatorial target to improve immune checkpoint therapy response
Authors: Liu Jielin , Anandhan Swetha , Basu Sreyashi , Chen Yulong , Goswami Sangeeta , Nagarajan Ashwat , Herbrich Shelley , Xiong Liangwen , Guan Baoxiang , Sharma Padmanee 
Published: April 2023

Abstract
Immune checkpoint therapy (ICT) has recently revolutionized the treatment paradigm for various types of cancer. However, despite the unprecedented safety and efficacy profile compared to traditional treatment options, many patients do not respond to ICT, highlighting the urgent need for novel strategies to improve ICT efficacy. Here, we used a pooled in vivo CRISPR knockout screening in a mouse bladder cancer model treated with immune checkpoint inhibitor to discover targets that may improve immunotherapy response. Our data identified Ptdss1, which encodes phosphatidylserine synthase 1, as a potential regulator of anti-PD-1 response. Depletion of Ptdss1 not only increased tumor cell immunogenicity and response to interferon gamma, but also facilitated development of an anti-tumor microenvironment. Ptdss1 depletion in tumor cells increased effector CD8+ T cells cytolytic function, decreased regulatory T cells activation and inhibitory function, increased frequency of iNOS+ myeloid cells and induced macrophage M2-to-M1 polarization. Ptdss1 knockdown induced changes in the tumor microenvironment were further amplified when combined with anti-PD-1 treatment, which translates into better tumor control and prolonged animal survival in mouse bladder cancer model. Together, our results provide insights on a new therapeutic strategy for overcoming resistance to immune checkpoint therapy through combination of PTDSS1 inhibition and PD-1 blockade.
Citation Format: Jielin Liu, Swetha Anandhan, Sreyashi Basu, Yulong Chen, Sangeeta Goswami, Ashwat Nagarajan, Shelley Herbrich, Liangwen Xiong, Baoxiang Guan, Padmanee Sharma. In vivo CRISPR screening identifies PTDSS1 as a potential combinatorial target to improve immune checkpoint therapy response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3277.
Abstract 3484: Oncohistone H2B-E76K alters gene expression & cellular phenotype in a bronchial epithelial cell line
Authors: Pereira Kimberly Espinoza , Bennett Richard L. , Shan Jixiu , Sarthy Jay , Licht Jonathan D. 
Published: April 2023

Abstract
The nucleosome is the basic unit of chromatin, comprising 147 bp of DNA wrapped around an octamer of core histone proteins H2A, H2B, H3 and H4. Compact chromatin acts as a barrier to gene expression and is a key property governing DNA replication and gene expression. Analyzing over 46,000 in cancer patient samples in cBioPortal, we characterized mutations located in canonical histone genes and found several recurrent missense mutations. Foremost among the identified mutations was a glutamate to lysine missense mutation at amino acid 76 of histone H2B (H2B-E76K) that disrupts histone H2B-H4 interaction. Previously, we demonstrated that exogenous expression of H2B-E76K disrupted nucleosome stability, altered chromatin accessibility, and gene expression. We developed a new model utilizing CRISPR “knock-in” technology to integrate the E76K mutation into the endogenous H2BC4 gene of the lung epithelial cell line BEAS-2B to create a homozygous and heterozygous H2B-E76K cell line. Although the mutant histone only accounts for about 2-5% of total histone H2B, expression of H2B-E76K catalyzed distinct changes in cell migration, proliferation, colony formation and gene expression. CUT&RUN technology revealed mutant histones broadly incorporate throughout the genome. Gene set enrichment analysis (GSEA) revealed that H2B-E76K homozygous cells displayed expression changes similar to polycomb repressive complex 1 (PRC1) disruption or oncogenic KRAS expression. Using available datasets, we discovered that expression of H2B-E76K caused increased expression of PTN, PKIB, and CDH2, genes important in migration, epithelial-mesenchymal transition (EMT), and adhesion pathways. Furthermore, analysis of chromatin accessibility changes indicated that increased accessibility was significant in and around genes governing cell migration. Notably, H2B-E76K significantly increased heterogeneity of gene expression as measured using scRNA-seq. Together these results indicate that mutations disrupting histone structure may create millions of dysfunctional nucleosomes and new sites of “open” chromatin, resulting in loss of nucleosome-mediated gene repression and/or altered interactions with regulators of chromatin, fundamentally changing cell growth and migration properties to favor tumorigenesis.
Citation Format: Kimberly Espinoza Pereira, Richard L. Bennett, Jixiu Shan, Jay Sarthy, Jonathan D. Licht. Oncohistone H2B-E76K alters gene expression & cellular phenotype in a bronchial epithelial cell line [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3484.
Abstract 3543: Mesenchymal stromal cells and tumor-associated macrophages modulate adrenergic to mesenchymal state switching in neuroblastoma
Authors: Lee Meng-Hua , Louault Kevin , Giannikou Krinio , Ding Xiangming , Yanovsky Alice , Park Jin-Seok , DeClerck Yves A. , Asgharzadeh Shahab 
Published: April 2023

Abstract
Neuroblastoma (NB), a common solid tumor of children, can adopt a lineage-committed adrenergic (ADRN) or an immature mesenchymal (MES) tumor cell type, which differs in phenotype, epigenetic landscape, transcription factors, and core regulatory circuitries. These cell types can spontaneously interconvert, but the mechanism remains largely unknown. Here, we hypothesize that the tumor-associated macrophages (TAM) and cancer-associated fibroblast (CAF) within the tumor microenvironment contribute to pro-tumorigenic factors production and drive switching from ADRN to MES state in neuroblastoma. We first demonstrate the ADRN and MES lineage identity of NB cell lines by Western blot and compared the control and NB cell lines co-cultured with mesenchymal stromal cells (MSC), the precursor cell of CAF, and monocyte in transwell. Initial experiments demonstrated the morphology of NB cell line CHLA255 and CHLA136 showing increased spreading area and spindle shape in TAM-CAF co-cultures compared to control cells. As compared to control cells, monocytes and MSC-CAF co-culture induced the MES lineage markers SOX9 and Notch1 of NB cell lines that had low basal SOX9 expression, with a reduction in protein levels of ADRN lineage markers PHOX2B, and GATA3. Next, single-cell RNA-sequencing was utilized to analyze the expression of TAM and CAF, and MES- and ADRN-signature genes of NB cells in NB-TAM-CAF co-cultures. Single-cell analyses of TAM-CAF co-cultured CHLA255 and CHLA136 demonstrated enrichment of MES signature over time providing clear evidence of mesenchymal differentiation of NB cells within a TME-rich environment. Pathway enrichment analyses reveal enrichment of pathways associated with extracellular matrix (ECM) deposition and epithelial to mesenchymal of TAM-CAF co-cultured NB cell lines. Our results suggested that the presence of CAF and TAM in the tumor microenvironment drives neuroblastoma ADRN: MES switch akin to that observed in epithelial: mesenchymal switch in adult tumors. ADRN-MES state switching has been shown relevant for tumor relapse and therapy resistance. Our studies point to a therapeutic vulnerability by targeting cells and pathways activated in the NB-TAM-CAF axis.
Citation Format: Meng-Hua Lee, Kevin Louault, Krinio Giannikou, Xiangming Ding, Alice Yanovsky, Jin-Seok Park, Yves A. DeClerck, Shahab Asgharzadeh. Mesenchymal stromal cells and tumor-associated macrophages modulate adrenergic to mesenchymal state switching in neuroblastoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3543.
Abstract 3902: Glutathione as a potential marker of tamoxifen resistance in breast cancer
Authors: Hamadneh Yazan I. , AlWahsh Mohammad , Alrawabdeh Jawad , Hergenröder Roland , Dahabiyeh Lina A. , Hamadneh Lama 
Published: April 2023

Abstract
Glutathione (GSH) is an antioxidant with an important protective intracellular role against reactive oxygen species. Increased glutathione level is associated with higher rates of metastases and a more aggressive behavior in breast cancer. This study aims to study the molecular and metabolic changes in glutathione synthesis in tamoxifen resistant (TAM-R) MCF-7 breast cancer cell lines.Methods: Three tamoxifen resistant MCF-7 cell lines were produced by using two methods. The first was achieved by treating the cells with tamoxifen and gradually increasing the amount until reaching a predetermined concentration of tamoxifen. The second was achieved by giving multiple fixed concentrations of tamoxifen, the third model was produced from the second by treating the cells with continuous 1µM of tamoxifen. mRNA and metabolites were extracted from the cell lines. cDNA was synthesized from the extracted mRNA, and gene expression of glutathione synthetase (GSS) was measured using real-time PCR. Nuclear Magnetic Resonance technique with PABO probe was used for metabolic profiling of extracted metabolites from the resistant and sensitive MCF-7cells and Chenomix software for quantification. Additionally, Kaplan Meier plotter (https://kmplot.com/) was used to predict the significance of GSS gene expression to overall survival of breast cancer patients. Results: A significant increase in glutathione accompanied with significant decrease in cysteine levels were found in TAM-R cells compared to control TAM sensitive cells. However, there was a 2 times reduction in the expression of GSS in TAM-R cells. Correlation of GSS gene expression among ER +ve, PR +ve patients who received tamoxifen in their therapy showed that its down regulation is significantly linked to poor overall survival (p-value 0.022 and HR of 0.7). Conclusion: The significant increase of glutathione in TAM-R cells may contribute to their increased resistance to oxidative stress and exhibition of a more aggressive behavior. Moreover, the decrease in GSS expression is a strong indicator of decreased glutathione synthesis in TAM-R cells as a result of cysteine depletion in the cells that was correlated to poor overall survival among BC patients. However, high glutathione levels in TAM-R cells could be due to increased glutathione regeneration in TAM-R cell lines compared to control.
Citation Format: Yazan I. Hamadneh, Mohammad AlWahsh, Jawad Alrawabdeh, Roland Hergenröder, Lina A. Dahabiyeh, Lama Hamadneh. Glutathione as a potential marker of tamoxifen resistance in breast cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3902.
Abstract 3954: Evaluation of long mononucleotide repeat markers for detection of microsatellite instability
Authors: Chen Suping , Lin John H. , Pallavajjala Aparna , Lotan Tamara L. , Bacher Jeffery W. , Eshleman James R. 
Published: April 2023

Abstract
Microsatellite instability (MSI) and mismatch repair immunohistochemistry are biomarkers of defective MMR (dMMR) that predict response to immune checkpoint inhibitor therapy in solid tumors. The microsatellites in the Promega MSI Analysis System Version 1.2 may not be ideal to detect MSI in certain cancer types. Long mononucleotide repeat (LMR) markers may improve detection of microsatellite instability in early colorectal lesions and non-colorectal cancers.In this study, we compared the performance of the current gold standard, MSI Analysis System Version 1.2 (Promega), which consists of 5 mononucleotide repeat markers (21-27 bases), with a new LMR kit (Promega), which consists of 4 markers from the MSI V1.2 panel and 4 LMR loci (52-60 bases). We studied five cohorts including 24 MMR proficient (pMMR) and 24 dMMR colorectal cancer (CRC) samples, 24 pMMR and 42 dMMR endometrial cancer (EC) samples, 12 dMMR prostate cancer (PC) samples, 22 MSI-high (MSI-H) samples of other cancer types, and 12 MSI-low (MSI-L) samples, where MMR status was confirmed by immunohistochemical (IHC) staining and/or MSI Analysis System Version 1.2.The specificity and sensitivity of the LMR MSI panel for dMMR detection were both 100% in CRC. The specificity of the MSI V1.2 and LMR MSI panels in EC was both 100%, and the sensitivity was 88% versus 98%, respectively. The 22 MSI-high (MSI-H) samples of other cancer types, these include cholangiocarcinoma, appendix, duodenal, pancreatic and gastric cancer, which were previously classified as MSI-H by using the MSI V1.2 panel were also classified as MSI-H by using the LMR MSI panel. Among 12 samples that were previously classified as MSI-L by the MSI V1.2 panel, 9 of the samples were classified as MSI-L, and 3 of the samples were diagnosed as MSI-H using the MSI LMR panel. The LMR panel has performed well on 80 samples over the past 6 months.The LMR MSI panel is highly concordant with the MSI V1.2 panel for dMMR detection in colorectal cancer and showed increased sensitivity in endometrial cancer. The LMR MSI panel showed improved dMMR detection in non-colorectal cancers.
Citation Format: Suping Chen, John H. Lin, Aparna Pallavajjala, Tamara L. Lotan, Jeffery W. Bacher, James R. Eshleman. Evaluation of long mononucleotide repeat markers for detection of microsatellite instability. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3954.
Abstract 3969: Screening of kinase inhibitors as bioenergetic metabolism modulator using the XF Real-Time ATP Rate Assay
Authors: Kam Yoonseok , Winer Lisa , Romero Natalia 
Published: April 2023

Abstract
Cancer cells are metabolically reprogrammed through tumor initiation and progression, and there are increasing developments in cancer therapies exploiting the potential metabolic vulnerability. A better understanding of cancer cell metabolic regulation can also contribute to modulating the harsh tumor microenvironment, which strongly affects the efficacy of emerging anti-cancer immunotherapies. As one of the critical contributors to cancer therapy design, there is increasing demand for time-efficient and reliable analytic tools when searching for drugs and genes modulating cancer cell metabolism. The XF Real-Time ATP Rate Assay measures ATP production from glycolysis and mitochondrial respiration simultaneously and provides a quantitative overview of the bioenergetic phenotype of the cells. By using ATP production rate as a universal unit of bioenergetic metabolism, this assay quickly detects metabolic modulations induced by chemical stimuli or genetic modifications. It allows the identification of potential targets for therapy design. In this study, we used the Seahorse XF Pro Analyzer combined with the XF ATP Rate assay to screen 80 kinase inhibitors for the suppressive effects on energy metabolism and/or inducing a metabolic phenotype shift in THP-1 cells, a monocytic leukemia cell line, using PBMC as the control. We identified four mitochondrial and two glycolytic suppressors using the screening and dose-response views available in Seahorse Analytics, a cloud-based data analysis tool for Seahorse XF assays. These compounds showed moderate or no effects on the net ATP production rates but induced a significant shift in the metabolic phenotype of THP-1 cells. Among the selected kinase inhibitors, AG-879 (ErbB2 inhibitor), SU-1498 (VEGFR inhibitor), and U-0126 (MEK1/2 inhibitor) showed the most potent inhibitory effect on mitochondrial energy production in THP-1 cells. Dose-response studies indicated that SU-1498 and U-0126 have higher potency in THP-1 than PBMC, and thus they can be considered good cancer-cell targets for mitochondrial suppressors. In contrast, AG-879 showed a similar or higher inhibitory effect on PBMC even though it is the most potent mitochondrial suppressor among the selected compounds. These results demonstrate that the XF Real-Time ATP Rate Assay can be used as a primary assay for screening and validating drug candidate(s) targeting the bioenergetic metabolism of cancer cells.
Citation Format: Yoonseok Kam, Lisa Winer, Natalia Romero. Screening of kinase inhibitors as bioenergetic metabolism modulator using the XF Real-Time ATP Rate Assay. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3969.
Abstract 3970: NCG-hIL15 humanized mice: an ideal model for human immune reconstitution of NK cells
Authors: Liu Xing , Wu Meirong , Wang Huiyi , Yu Weiwei , Xu Jianming , Sun Hongyan , Ju Cunxiang , Wang Hongyu , Chen Santi Suryani , Li Zhiying , Moore Mark Wade , Zhao Jing , Gao Xiang 
Published: April 2023

Abstract
Introduction: IL-15 is a four α-helix bundle cytokine which is produced by dendritic cells, monocytes, and epithelial cells. IL-15 is necessary for the development, survival, and activation of natural killer (NK) cells. NK cells are unable to persist in immunodeficient NCG mice reconsituted with human NK cells, but after knocking in human IL-15 (hIL-15), NCG-hIL15 mice can support the reconstitution and survival of human NK cells.
Results: Compared with NCG mice, the level of hIL-15 was significantly increased in NCG-hIL15 mice. After transplanting human PBMC (huPBMC) or NK (huNK) cells into NCG-hIL15 mice, the peripheral blood level of NK cells in huNK-NCG-hIL15 mice was much higher than in huPBMC-NCG-hIL15 mice. The expression of perforin in peripheral blood of huNK-NCG-hIL15 mice was significantly higher than that in huPBMC-NCG-hIL15 mice. Considering the obvious ADCC of rituximab acting on Raji cells in vitro, we evaluated the efficacy of rituximab in huNK-NCG-hIL15 mice subcutaneously engrafted with Raji cells. Rituximab significantly inhibited the tumor growth in huNK-NCG-hIL15 mice.
Conclusion: NCG-hIL15 is a great mouse model to evaluate the anti-tumor efficacy of drugs targeting human NK cells without the interference of T cells.
Citation Format: Xing Liu, Meirong Wu, Huiyi Wang, Weiwei Yu, Jianming Xu, Hongyan Sun, Cunxiang Ju, Hongyu Wang, Santi Suryani Chen, Zhiying Li, Mark Wade Moore, Jing Zhao, Xiang Gao. NCG-hIL15 humanized mice: an ideal model for human immune reconstitution of NK cells. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3970.