bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2885: RASSF1A133Sresulting from the prevalent SNP rs2073498 is associated with Treg defects
Authors: Xu Haonan , Jones Keaton , Lang Cameron , Lanfredini Simone , Hughes Sophie , O'Neill Eric 
Published: April 2023

Abstract
Rs2073498 is a prevalent (~10% population) single nucleotide polymorphism (SNP) that leads to A133S missense mutation in tumor suppressor and Hippo Signaling Pathway scaffold protein RASSF1A. Recent reports have illustrated the crucial involvement of Hippo pathway proteins in lymphocyte recruitment, differentiation, and function. Using a BL/6 mouse model engineered with alanine-to-serine point mutation, we showed that RASSF1A133S is associated with systematic defects in regulatory T cells (Tregs). When blood was phenotyped through a 17-color spectral flow cytometry panel, both RASSF1A133S/WT and RASSF1A133S/A133S carriers had a smaller circulatory CD25+FoxP3+ Treg pool than WT controls. Magnetically sorted splenic T cells were also stimulated with PMA/Ionomycin ex vivo, and fewer Tregs from A133S carriers were expressing anti-inflammatory cytokine IL-10. Preliminary results further demonstrated that RASSF1A133S/WT has fewer intratumor FoxP3+ Tregs in subcutaneously injected MC38 colon adenocarcinoma tumor models. In contrast, A133S did not have any significant effects on thymic T cell maturation states, splenic T cell naïve/memory phenotypes, or Treg survival fitness measured by Fas/FasL and BCL-2 expression. Ex vivo stimulation also demonstrated that A133S carriers retain similar IL-2 sensitivity and phospho-STAT5 response when compared to the controls, although RASSF1 downstream kinases MST1/2 have been reported to amplify IL-2-STAT5 signaling in Tregs (Shi et al., 2018). These results collectively suggest that RASSF1A133S may leads to Treg imbalance and predispose rs2073498 carriers to Treg mediated autoimmune risks.
Citation Format: Haonan Xu, Keaton Jones, Cameron Lang, Simone Lanfredini, Sophie Hughes, Eric O'Neill. RASSF1A133Sresulting from the prevalent SNP rs2073498 is associated with Treg defects [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 2885.
Abstract 2941: ROR1 targeted 4-1BB costimulatory bispecific antibody, ABL102, exhibits potent in vitro and vivo antitumor activity and superior safety profile
Authors: Lee Yangsoon , Park Kyeong-Su , Son Wonjun , Kim Sora , Youn Hyunseong , Yoo Jiseon , Lee Hanbyul , Won Jonghwa 
Published: April 2023

Abstract
ROR1, a member of the ROR (Receptor Tyrosine Kinase-Like Orphan Receptor)-family, is overexpressed in the process of embryo and fetal development, and controls cell polarity, cell migration and neurite growth. The expression is gradually reduced as development progresses, and it is hardly expressed in adults, but the overexpression of ROR1 is observed in various blood and solid cancer cells, so it is classified as an oncofetal gene. ABL102, a First-in-Class bispecific antibody targeting ROR1 and 4-1BB, elicits superior T cell activation by tumor specific T cell engagement through ROR1 dependent 4-1BB clustering. Our data showed that tumor target dependents binding of ROR1 and costimulatory 4-1BB by ABL102 induced 4-1BB activation in cell-based 4-1BB bioassay. ABL102 lead to IFN-γ secretion and tumor cell killing with a ROR1 dependent manner in co-culture assay with tumor cells and human PBMC. In h4-1BB knock-in mouse model bearing hROR1-expressing tumors, ABL102 potently inhibited tumor progression with a high rate of complete remission (CR). Mice with CR were further protected from the rechallenge of previously exposed tumors after 3 months of cessation of ABL102 treatment, implicating that immunological memory might be generated. In 4-week pilot toxicity study using cynomolgus monkeys, no ABL102-related toxicity was observed up to 100mg/kg, including mortality, body weight, hematology, liver toxicity, clinical chemistry and pathology, indicating a favorable safety profile. In conclusion, ABL102 exhibited potent in vitro and vivo anti-tumor activity and it was well tolerated and safe in the NHP toxicity study. These results strongly suggest that ABL102 is promising therapeutics for ROR1 positive cancer patients.
Citation Format: Yangsoon Lee, Kyeong-Su Park, Wonjun Son, Sora Kim, Hyunseong Youn, Jiseon Yoo, Hanbyul Lee, Jonghwa Won. ROR1 targeted 4-1BB costimulatory bispecific antibody, ABL102, exhibits potent in vitro and vivo antitumor activity and superior safety profile [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 2941.
Abstract 295: Targeting spermine synthase triggers lipid metabolism reprogramming as a new therapeutic option to combat colorectal cancer
Authors: Ma Murong , Guo Yubin , Ye Qing , Deng Pan , He Daheng , Wang Chi , She Qing-Bai 
Published: April 2023

Abstract
Dysregulation of polyamine metabolism has been linked to the development of colorectal cancer (CRC). Our recent work demonstrates that spermine synthase (SMS), a polyamine biosynthetic enzyme that converts spermidine to spermine, is overexpressed in CRC, which is required for balancing cellular spermidine levels to facilitate CRC tumorigenesis (Nat Commun 11:3243, 2020). Our findings reveal SMS as an attractive therapeutic target in CRC; yet, genetic depletion of SMS expression only shows a limited antitumor effect. Using unbiased metabolomics and transcriptomics analyses, we identified a lipid metabolism reprograming as among the most impacted metabolic change by SMS depletion in CRC cells. Specifically, SMS depletion significantly altered long-chain fatty acid, triacylglycerol and phospholipid metabolism. Furthermore, targeted inhibition of SMS significantly increased the number of lipid droplets and the levels of long-chain fatty acid acylcarnitines for oxidative phosphorylation in mitochondria, and upregulated expression of genes associated with increased mobilization of polyunsaturated fatty acids and the genes associated with lipid peroxidation for induction of ferroptosis, an iron-dependent form of nonapoptotic cell death. The glutathione peroxidase 4 (GPX4) is a key negative regulator of ferroptosis by neutralizing lipid peroxides. Notably, pharmacological inhibition of GPX4 or its upstream regulator system xc − in combination with genetic depletion or pharmacologic inhibition of SMS synergistically caused lipid peroxidation leading to ferroptosis induction and marked suppression of CRC cell growth. Collectively, these findings highlight lipid metabolism reprograming as an adaptive response to targeted inhibition of SMS to enable CRC cell survival, which represents an Achilles’ heel that can be exploited for potential effective therapy for CRC.
Citation Format: Murong Ma, Yubin Guo, Qing Ye, Pan Deng, Daheng He, Chi Wang, Qing-Bai She. Targeting spermine synthase triggers lipid metabolism reprogramming as a new therapeutic option to combat colorectal 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 295.
Abstract 3020: Machine learning-based cluster analysis of immune cell subtypes and breast cancer survival
Authors: Wang Zhanwei , Katsaros Dionyssios , Wang Junlong , Biglio Nicholetta , Hernandez Brenda Y. , Fei Peiwen , Lu Lingeng , Risch Harvey , Yu Herbert 
Published: April 2023

Abstract
Background: Host immunity involves various immune cells working in concert to achieve balanced immune response. Host immunity interacts with tumorigenic process impacting disease outcome. Clusters of different immune cells may indicate specific host-tumor interplay. Identifying the clusters may reveal unique host immunity in response to tumor growth.
Methods: CIBERSORT was used to estimate relative abundances of 22 immune cell types in 3 datasets, METABRIC, TCGA, and our study. The cell type data in METABRIC were analyzed for cluster using unsupervised hierarchical clustering (UHC). The UHC results were employed to train machine learning models, random forest (RF), deep neural network (DNN), stepAIC, and elastic net. Kaplan-Meier and Cox regression survival analyses were performed to assess cell clusters in association with relapse-free and overall survival. Differentially expressed genes (DEGs) by immune cell clusters were interrogated with IPA for molecular signatures.
Results: UHC analysis identified two distinct immune cell clusters, clusters A (83.2%) and B (16.8%). Memory B cells, plasma cells, CD8 positive T cells, resting memory CD4 T cells, activated NK cells, monocytes, M1 macrophages, and resting mast cells were more abundant in clusters A than B, whereas regulatory T cells and M0 and M2 macrophages were more in clusters B than A. Patients in cluster A had favorable survival compared to those in cluster B. Similar survival associations were also observed in TCGA and our study when using a RF model trained with the UHC results. The survival associations were independent from clinicopathological variables. IPA analysis showed that pathogen-induced cytokine storm signaling pathway, phagosome formation, and T cell receptor signaling were related to the cell type clusters.
Conclusions: Our finding suggests that different immune cell clusters may indicate distinct immune responses to tumor growth, suggesting their potential for disease management.
Citation Format: Zhanwei Wang, Dionyssios Katsaros, Junlong Wang, Nicholetta Biglio, Brenda Y. Hernandez, Peiwen Fei, Lingeng Lu, Harvey Risch, Herbert Yu. Machine learning-based cluster analysis of immune cell subtypes and breast cancer survival [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 3020.
Abstract 3153: Prediction of metabolites from cancer-associated fibroblasts that can have profound effects on cancer cells
Authors: Jung Hae Deok , Sung Yoo Jin , Ryu Jae Yong , Kim Hyun Uk 
Published: April 2023

Abstract
Cancer-associated fibroblasts (CAFs) are the most abundant component of tumor microenvironment (TME) that is an ensemble of non-cancerous cells surrounding cancer cells. In particular, CAFs are known to have tumor-assisting functions, which may promote active growth and survival of the interacting cancer cells through their metabolic reprogramming despite being in a harsh environment (e.g., hypoxia or low pH). In this regard, CAF-derived metabolites are expect to have profound effects on metabolism of the cancer cells. To identify novel CAF-derived metabolites that may heavily influence the cancer cells, CAF-specific genome-scale metabolic models (GEMs) were reconstructed and simulated. GEM is a computational model that can predict a metabolic state in a cell-specific manner by integrating omics data (e.g., RNA-seq data). In this study, a total of six GEMs were reconstructed by integrating RNA-seq data from one normal fibroblast, originating from pancreas, and five CAFs associated with breast, colon, skin, lung, and pancreatic tumors. Simulation of the GEMs predicted 20 metabolites that appeared to be heavily used by all the five CAF GEMs in comparison with the one normal fibroblast GEM. Such metabolites were expected to be significantly associated with establishment of TME that is favorable for the cancer cells’ growth. Some of these metabolites are associated with pyrimidine metabolism, fatty acid metabolism, and primary bile acid biosynthesis. Upon experimental validation, the predicted metabolites are expected to help better understand CAFs and TME in terms of metabolites, and also provide clues for identifying effective drug targets for cancer treatment.
Citation Format: Hae Deok Jung, Yoo Jin Sung, Jae Yong Ryu, Hyun Uk Kim. Prediction of metabolites from cancer-associated fibroblasts that can have profound effects on cancer 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 3153.
Abstract 317: Particulate matter accumulates chromosomal instability during mitosis
Authors: Ryu Jaewook , Kim Ja-Eun 
Published: April 2023

Abstract
Particulate matter (PM), a major component of outdoor air pollution triggers genotoxicity as well as cytotoxicity. Although the harmful effects of PM on DNA damage and its carcinogenic risk have been thoroughly studied, the detailed mechanism by which PM affects chromosomal stability remains unclear. Maintenance of chromosome is finely monitored during mitotic phase through multiple proteins and structures. The present study shows that treatment of urban particulate matter (UPM) inhibited proliferation of lung cells through the accumulation of chromosomal instability which is determined by the formation of multinucleation and macronucleation. In particular, PM treatment prolonged mitotic duration. This delay in mitotic progression resulted from inactivation of Aurora B at prometaphase and metaphase, causing a failure in dynamic stabilization of kinetochore-microtubule attachment. In addition, ingression rate of cleavage furrow and actin clearing from polar cortex were significantly reduced at telophase. It indicates that dysregulation of spatiotemporal dynamics of mitotic proteins and structures finally disturbs cytokinetic division. Overall, PM leads to accumulation of chromosomal instability, finally contributing to its carcinogenicity.
Citation Format: Jaewook Ryu, Ja-Eun Kim. Particulate matter accumulates chromosomal instability during mitosis [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 317.
Abstract 3274: Novel cell-based bioassays for mono- and multi-specific antibodies targeting PD-1/PD-L1 for combination immunotherapy
Authors: Wang Jun , Gilden Julia , Garvin Denise , Stecha Pete , Hartnett Jim , Fan Frank , Cong Mei , Grailer Jamison 
Published: April 2023

Abstract
Programmed cell death protein 1 (PD-1) is an immune checkpoint (IC) receptor that negatively regulates T cell function. Blocking the interaction of PD-1 with its ligands PD-L1 or PD-L2 unleashes the immune system and enhances anti-tumor responses. Immunotherapy using PD-1 or PD-L1 blocking antibodies has led to a paradigm shift in cancer drug discovery, due to its durable effect against a wide variety of cancers. However, despite its tremendous clinical success in cancer treatment, a significant fraction of patients and tumor types remain unresponsive to this therapy. This has led to the development of combination therapies linking PD-1 checkpoint inhibitors with inhibitors of several other IC receptors. A major challenge in immunotherapy drug development is the lack of quantitative and reproducible functional assays. Existing methods rely heavily on primary immune cells are highly variable and labor-intensive. Here, we report the development of a suite of cell line-based reporter bioassays for monoclonal antibodies targeting human PD-1/PD-L1, or bispecific antibodies targeting PD-1/PD-L1 and a co-stimulatory receptor (e.g., 4-1BB, OX40, ICOS) or an immune inhibitory receptor (e.g., CTLA-4, LAG-3, TIGIT). A mouse PD-1/PD-L1 assay and a human PD-1/PD-L2 assay are also developed and can be used in parallel with human PD-1/PD-L1 assay to enable preclinical studies and assess assay specificity. Each of these assays consist of two engineered cell lines: a T effector cell line that express a luciferase reporter driven by specific promoter/response elements responding to the intracellular signals mediated by the T cell receptor (TCR), with modulation from PD-1 and the second immune receptor, and an engineered artificial antigen presenting cell (aAPC). Importantly, these combination bioassays demonstrate the synergetic effect of PD-1 blockade with blockade of a second IC inhibitor receptor or activation of a costimulatory receptor, thus reflecting the mechanisms of action for the therapeutic antibodies of interest. The bioassays are sensitive and quantitative, are prequalified according to ICH guidelines, and demonstrate the performance characteristics (specificity, precision, accuracy, and linearity) to be used as potency assays for product release and stability studies during immunotherapy drug development.
Citation Format: Jun Wang, Julia Gilden, Denise Garvin, Pete Stecha, Jim Hartnett, Frank Fan, Mei Cong, Jamison Grailer. Novel cell-based bioassays for mono- and multi-specific antibodies targeting PD-1/PD-L1 for combination immunotherapy [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 3274.
Abstract 3282: Regorafenib enhance PD-L1 expression via ATM activation and evaluate the therapeutic efficacy of combining PD-L1 antibody on bladder cancer
Authors: Pai Kai-Jen , Chiang I-Tsang , Hsu Fei-Ting , Tsai Jai-Jen 
Published: April 2023

Abstract
Bladder cancer is one of the most common cancer in urinary system in Taiwan. According to Ministry of Health and Welfare’s research, bladder cancer plays 15th leading causes of death in Taiwan in 2020. Recently immune checkpoint inhibitor (ICI) therapy show several benefits on preventing T cell exhaustion, accumulating evidences showed ICI therapy still remain some limitation, including unable to regulated immunosuppressor cells and tumor microenvironment (TME) related elements which might lead to ICI therapy dysfunction. Recently, study report that DNA damage may activate the innate immune response and improve ICI efficacy. Thus, regulating DNA damage or illustrate the role of DNA damage related factor may bring the twilight to immunotherapy. To identify the possible combination methods with ICIs, we used MB49 cells and animal model to test the combination property of regorafenib (a multiple receptor tyrosine kinase inhibitor) and 10F.9G2 (a PD-L1 monoclonal antibody). Our research illustrated the mechanism between regorafenib and PD-L1, we proved that regorafenib-induced regulated PD-L1 is associated with ATM activation. TUENL assay showed regorafenib are able to activate ATM by causing DNA break and thus enhance the expression of PD-L1 on tumor surface. This effect could be an important step to open the interaction potential of PD-L1 antibodies and thus enhance its efficacy. Through the interaction analysis of miRNA targeting gene (RNA22), we found that IDO1 mRNA could specifically interact with endogenous miR-124. Here, the propose mechanism in our research is that regorafenib may downregulate IDO1 expression via increasing of endogenous miR-124 expression. In animal model, the combination therapy showed extraordinary therapeutic effect, not only dramatically decreased tumor volume, but also upregulating the positive TME components, such as CD8+T cells and M1 macrophage. Though regorafenib may induce PD-L1 expression, regorafenib still showed several therapeutic benefits, including downregulating immunosuppressive factors, such as IDO1, VEGF, and suppressing the accumulation of regulatory T cells, myeloid-derived suppressor cells and also repolarizing macrophage from M2-to-M1⋯etc. In conclusion, this study points out the combination therapy of regorafenib and anti-PD-L1 has present several benefits to bladder cancer patients and is associated with miR-124/ATM signaling.
Citation Format: Kai-Jen Pai, I-Tsang Chiang, Fei-Ting Hsu, Jai-Jen Tsai. Regorafenib enhance PD-L1 expression via ATM activation and evaluate the therapeutic efficacy of combining PD-L1 antibody on bladder 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 3282.
Abstract 3286: B-hCD94/hNKG2A mice provide a preclinical tool for evaluating therapeutic antibodies targeting human NKG2A
Authors: Shang Chengzhang , He Fang , Kuraguchi Mari , Zhang Jing , Lin Qingcong 
Published: April 2023

Abstract
The immune cell checkpoint NKG2A and its coreceptor, CD94, are expressed by many circulating NK cells and by a subset of CD8 T cells in tumors. When CD94/NKG2A recognizes the HLA-E-peptide complex, the protein tyrosine phosphatase SHP-1 is recruited to the signaling synapse, resulting in the delivery of inhibitory signals to the effector cells and inhibition of their immune activities. In preclinical mouse models, blocking antibodies against NKG2A restores the reactivity of these effector cells, resulting in better suppression of tumor growth. Thus, NKG2A targeting is currently being evaluated in the clinic to evaluate tumor cell killing. To evaluate the in vivo efficacy of anti-NKG2A in mice, we successfully generated a humanized CD94/NKG2A double knock-in mouse strain (B-hCD94/hNKG2A mice), in which the mouse CD94 and NKG2A genes are replaced by the corresponding human CD94 and NKG2A genes in situ in cis, respectively. Human CD94 and NKG2A mRNA and proteins were exclusively detectable by flow cytometry in homozygous humanized mice, confirming successful generation of the model. This model was used to demonstrate in vivo efficacy of monalizumab analog in suppressing the growth of MC38 tumor cells expressing human HLA-E (B-hHLA-E MC38). Furthermore, dual blockade of monalizumab and PD-L1 further suppressed B-hHLA-E MC38 tumor growth. Together, these data indicate that this double humanized model is an effective tool for evaluating novel anti-human NKG2A therapies, and warrants the generation of a quadruple humanized model (B-hPD-1/hPD-L1/hCD94/hNKG2A mice) to further evaluate the synergy of drugs blocking each checkpoint.
Citation Format: Chengzhang Shang, Fang He, Mari Kuraguchi, Jing Zhang, Qingcong Lin. B-hCD94/hNKG2A mice provide a preclinical tool for evaluating therapeutic antibodies targeting human NKG2A [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 3286.