bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB323: Deciphering the immunomodulatory role of IL-19 in glioblastoma-promoting ecosystem: Insights into glioblastoma stem cell-tumor-associated macrophage symbiosis
Authors: Lee Gilbert Aaron , Chen Cheng-Yu 
Published: April 2024

Abstract
Glioblastoma multiforme (GBM) stands out as a highly aggressive and resistant brain tumor, characterized by profound immunosuppression and chemoresistance, resulting in a dismal 5% survival rate at the five-year mark. Glioblastoma Stem Cells (GSCs) drive the progression of GBM, orchestrating tumor initiation, growth, and therapeutic resistance. The symbiotic interplay between GSCs and tumor-associated macrophages (TAMs) within hypoxic and perivascular niches is pivotal for sustaining tumorigenesis and immunosuppression. In this study, Interleukin-19 (IL-19), a member of the IL-10 family, was identified among the top five immune-related genes strongly associated with poor survival in patients with GBM from TCGA and Taiwan GBM cohorts. However, the function of IL-19 in glioblastoma is completely unknown. Genomic screening identified IL-19 as a predicted immunosuppressive cytokine in the peritumoral region, associated with poor survival in GBM patients. Blocking IL-19 inhibits both temozolomide (TMZ)-sensitive and TMZ-resistant tumor progression. Molecular studies revealed that IL-19 promotes TMZ-resistant GBM cell migration and invasion through a novel IL-19/β-catenin/WISP1 signaling. Single-cell transcriptome analysis showed that blocking IL-19 promotes T cell activation, upregulates the effector function of T cell subsets, and reprograms TAM subsets toward weakened pro-tumoral phenotypes with lower Arginase 1 expression. Silencing IL-19 significantly disrupts self-renewal GSC activity through a novel IL-19/S100A4/WISP1 signaling. Additionally, we identified that TAM-derived IL-19 positively regulates GSC self-renewal through the paracrine IL-19/WISP1 axis. Our study demonstrates IL-19 as a linchpin in the complex GSC-TAM symbiosis, leading to GSC maintenance and immunosuppression, providing critical insights into the immune landscape orchestrated by GSC-TAM symbiosis
Citation Format: Gilbert Aaron Lee, Cheng-Yu Chen. Deciphering the immunomodulatory role of IL-19 in glioblastoma-promoting ecosystem: Insights into glioblastoma stem cell-tumor-associated macrophage symbiosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB323.
Abstract LB330: CWH43 as a prognostic marker and therapeutic target in colorectal cancer
Authors: Lee Cheng-Chin , Chang Yu-Jia , Huang Chien-Yu 
Published: April 2024

Abstract
Colorectal cancer (CRC) remains a significant global health issue, particularly challenging due to the poor prognosis of its metastatic form. This highlights the critical need for novel and effective therapeutic targets to manage disease progression. A key focus of our research is the Cell Wall Biogenesis 43 C-Terminal Homolog (CWH43), which plays an essential role in GPI anchor biosynthesis and lipid remodeling, crucial for attaching membrane proteins to cell membranes. Our study aimed to clarify the function of CWH43 in CRC progression and evaluate its potential as a therapeutic target. Through an integrated bioinformatics analysis using public cancer databases, coupled with experimental validations in CRC cell models, we noted a conspicuous decrease in CWH43 mRNA levels in CRC tissues compared to normal tissue. This decrease in CWH43 expression correlated with poorer prognoses in CRC patients. In our experimental findings, we discovered that suppressing CWH43 led to increased proliferation, migration, and invasiveness of CRC cells, whereas its overexpression inhibited these processes. Notably, we observed elevated levels of CWH43 in CRC patients who showed a lower response to chemotherapy. Particularly in advanced-stage CRC patients (T4 and N2), high CWH43 expression correlated with reduced overall survival and shorter progression-free intervals, suggesting a potential association with chemotherapy resistance. In our cellular experiments, overexpression of CWH43 in CRC cells resulted in decreased sensitivity to chemotherapy drugs like CPT11, 5-FU, and oxaliplatin, which was consistent with a reduction in the expression of apoptosis-related markers. Additionally, there was a notable negative correlation between CWH43 expression and radiation sensitivity. Our Gene Set Enrichment Analysis (GSEA) revealed a significant connection between CWH43 and pathways involved in oxidative phosphorylation and fatty acid metabolism, indicating its role in regulating ferroptosis. We also demonstrated that overexpressing CWH43 in CRC cells increases the levels of multiple ferroptosis suppressors. Importantly, the use of ferroptosis inducers appeared to counteract the chemotherapy resistance influenced by CWH43. Based on these findings, we propose that CWH43 plays a role in inhibiting ferroptosis, contributing to therapeutic resistance in CRC. Therefore, targeting CWH43 could be a promising strategy for developing ferroptosis-inducing therapies, offering a new avenue for the treatment of CRC, especially in cases resistant to traditional therapies.
Citation Format: Cheng-Chin Lee, Yu-Jia Chang, Chien-Yu Huang. CWH43 as a prognostic marker and therapeutic target in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB330.
Abstract LB340: Harnessing the gp70 endogenous retrovirus envelope protein as a universal tumor antigen for T cell therapy in mice
Authors: Lehar Sophie M. , Roy Srirupa , Liao Lisa , Chen Haiyin , Chen Yongmei , Tleugabulova Mayra Cruz , Janezic Eric , Madjidi Azadeh , Jones Tamaki , Javinal Vincent , Ziai James , Mellman Ira , Schartner Jill , Shaw Andrey 
Published: April 2024

Abstract
FDA approval for chimeric antigen receptor (CAR) T cell therapies targeting hematological cancers has unleashed the potential of utilizing live T cells as therapeutics. However, CAR-mediated targeting of solid tumors is currently limited by a paucity of suitable tumor antigens that are both specific and highly expressed on the tumor cell surface. In this report we explore the possibility of harnessing tumor-specific expression of endogenous retroviruses (ERVs) as a universal target for CAR T cell therapy. We found that gp70, the envelope protein from a murine ERV, is highly expressed on the surface of tumor cell lines derived from a diverse array of murine tumor types. We utilized the B16 melanoma model as a representative poorly inflamed tumor that does not respond to existing immunotherapies to examine efficacy of gp70 CAR T cells. T cells engineered to express a gp70 CAR suppress tumor growth in vivo and recognize B16 tumor cells with improved sensitivity compared to T cells expressing two previously described dominant tumor antigens (gp100 or P15e) due to low expression of MHC-I on B16 tumors. Co-incubation of B16 tumor cells with gp70 CAR T cells results in upregulation of MHC-I on the tumor cell surface suggesting that in addition to killing tumor cells directly, gp70 CAR T cells could facilitate recognition of the tumor by endogenous T cells through local release T cell derived IFNγ. We postulate that utilization of CAR T cells specific for cell surface ERV envelope proteins offers a promising strategy that could be harnessed to achieve local release of T cell derived payloads specifically within the tumor microenvironment.
Citation Format: Sophie M. Lehar, Srirupa Roy, Lisa Liao, Haiyin Chen, Yongmei Chen, Mayra Cruz Tleugabulova, Eric Janezic, Azadeh Madjidi, Tamaki Jones, Vincent Javinal, James Ziai, Ira Mellman, Jill Schartner, Andrey Shaw. Harnessing the gp70 endogenous retrovirus envelope protein as a universal tumor antigen for T cell therapy in mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB340.
Abstract LB343: Golgihi T cells exhibit reduced susceptibility to exhaustion and improved tumor control
Authors: Oberholtzer Nathaniel , Chakraborty Paramita , Kassir Mohamed Faisal , Dressman James , Hedley Zacharia , Scurti Gina , Gooz Monika , Ball Lauren E. , Hill Elizabeth , Mehta Anand S. , Maldonado Eduardo N. , Nishimura Michael I. , Ogretmen Besim , Mehrotra Shikhar 
Published: April 2024

Abstract
The role of tumor microenvironment mediated disruption of Golgi architecture and function,termed Golgi stress, in the regulation of T cell survival and function are largely unknown. Here weshow that the disruption of Golgi architecture, identified by the decreased expression of GM130,was reverted upon treatment with hydrogen sulfide (H2S) donor GYY4137, or over-expressingcystathionine β-synthase (Cbs), an enzyme involved in the biosynthesis of endogenous H2S -that promoted stemness, antioxidant capacity and exhibited increased protein translationmediated in part by ER-Golgi shuttling of Peroxiredoxin-4. In in vivo models of melanoma andlymphoma, anti-tumor T cells conditioned ex vivo with exogenous H2S or overexpressing Cbsdemonstrated superior tumor control upon adoptive transfer. Further, Golgihi T cells, with highGolgi content, exhibited unique metabolic and glycation signature with enhanced anti-tumorcapacity. These data suggest that strategies to mitigate Golgi network stress or using Golgihitumor-reactive T cells can improve tumor control upon adoptive transfer.
Citation Format: Nathaniel Oberholtzer, Paramita Chakraborty, Mohamed Faisal Kassir, James Dressman, Zacharia Hedley, Gina Scurti, Monika Gooz, Lauren E. Ball, Elizabeth Hill, Anand S. Mehta, Eduardo N. Maldonado, Michael I. Nishimura, Besim Ogretmen, Shikhar Mehrotra. Golgihi T cells exhibit reduced susceptibility to exhaustion and improved tumor control [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB343.
Abstract LB348: Discovery and in vitro efficacy validation of anti-CD39 monoclonal antibody for improving the tumor microenvironment
Authors: Yu Seonmi , Park Wanki , Song Jaeho , Kim Sooyoung , Park Bumchan 
Published: April 2024

Abstract
In the tumor microenvironment (TME), the accumulation of adenosine inhibits anti-tumor immune responses, thereby reducing the effectiveness of immune-based cancer therapies. CD39 is involved in inducing excessive adenosine production in tumor cells and immune cells, causing an immune-suppressive environment. As a result, cancer cells are able to evade the immune system, and immune cells are impaired in their ability to kill cancer cells. Therefore, the discovery of outstanding antibodies targeting CD39 has great potential for cancer immunotherapy. To this end, we have discovered antibodies that effectively inhibit the hydrolysis of ATP to adenosine.We confirmed the binding affinity of the anti-CD39 mAb to the CD39 antigen. BLI measurements revealed that anti-CD39 mAb had binding kinetics of KD = 9.40 x 10-11 M, which is better than those of comparative antibodies, competitor 1 (2.39x10-10 M) and competitor 2 (2.27x10-9 M). The cell binding affinity of anti-CD39 mAb was evaluated using SK-MEL-28 cells, which endogenously express high levels of surface CD39. The results showed that the anti-CD39 mAb exhibited superior cell binding affinity compared to the two comparative antibodies. Furthermore, anti-CD39 mAb demonstrated greater efficacy in inhibiting ATP hydrolysis by membrane CD39 and soluble CD39 when compared to the comparative antibodies. In vitro functional assays using human PBMCs demonstrated that inhibiting CD39 enhances T cell proliferation. The anti-CD39 mAb showed superior efficacy in promoting proliferation in CD4+ cells compared to the competitor antibody. Similarly, in CD8+ cells, anti-CD39 mAb exhibited more efficacy compared to competitor 1 antibody. In conclusion, our data indicates that anti-CD39 mAb exhibits excellent characteristics, including superior antigen binding affinity, inhibitory efficacy of ATP hydrolysis and promotion of T cell proliferation. In the future, we will validate the efficacy and stability of this antibody in preclinical studies. The use of this antibody is expected to contribute to immune-based cancer therapy by inhibiting the generation of adenosine in the tumor microenvironment.
Citation Format: Seonmi Yu, Wanki Park, Jaeho Song, Sooyoung Kim, Bumchan Park. Discovery and in vitro efficacy validation of anti-CD39 monoclonal antibody for improving the tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB348.
Abstract LB358: Program and epigenetic control of stemness and exhaustion of tumor infiltrating CD8+ T lymphocyte
Authors: Avram Dorina , Shaw Timothy , Pilon-Thomas Shari , Silvane Leonardo , Zelenka Tomas 
Published: April 2024

Abstract
Tumor infiltrating CD8+ T lymphocytes (TILs) develop a state of exhaustion, become terminally exhausted (Ttex) and fail to control tumor growth through cytolytic activity. At an early stage, however, progenitors of exhausted (pTex) TILs are renewable and still reprogrammable, and can generate efficient cytolytic effector cells. pTex highly express stemness program genes. There is a high interest in understanding the mechanisms that control stemness and exhaustion programs of TILs. In the current study we investigated the consequences of the removal of the transcription factor (TF) BCL11B in TILs on the control of the stemness and exhaustion programs, their epigenetics landscape, and the impact on the pTex versus Ttex TIL status. Using scRNAseq, bulk RNAseq and epigenomics approaches, we positioned BCL11B upstream of essential TFs of the stemness and exhaustion programs, as well as of the cytolytic activity program. BCL11B-/- CD8+ TILs have increased stemness and elevated effector program, but reduced exhaustion, and they promoted a superior response compared to WT TILs, restricting tumor growth. Importantly, evaluation of BCL11B KO signature in patients with metastatic melanoma treated with check point inhibitors, show a more favorable response and survival in the patients with enriched BCL11B KO TIL signature. Thus these results indicate that BCL11B constitutes a promising target for therapeutic intervention in cancer cell therapies to sustain stemness, cytolytic activity and reduce exhaustion.
Citation Format: Dorina Avram, Timothy Shaw, Shari Pilon-Thomas, Leonardo Silvane, Tomas Zelenka. Program and epigenetic control of stemness and exhaustion of tumor infiltrating CD8+ T lymphocyte [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB358.
Abstract LB360: Establishment of predictive biomarkers for carcinogenesis in ulcerative colitis using RNA editing analyses
Authors: Takahashi Toshiaki , Shigeyasu Kunitoshi , Kondo Yoshitaka , Umeda Hibiki , Moriwake Kazuya , Kayano Masashi , Nitta Kaori , Teraishi Fuminori , Umeda Yuzo , Tazawa Hiroshi , Fujiwara Toshiyoshi 
Published: April 2024

Abstract
Background: Ulcerative colitis (UC) is a chronic inflammatory disease continuous from the rectum. We previously reported that chronic inflammation may induce the RNA-editing enzyme ADAR1 and promote carcinogenesis (Journal of Crohn's and Colitis, 2023). However, the relationship between RNA editing and carcinogenesis in UC remains unresolved because we could not identify specific RNA editing sites. Therefore, in this study, we performed a new comprehensive RNA analysis using RNA sequencing to clarify the role of RNA editing in the carcinogenesis process in UC and to construct a prediction model of carcinogenic risk.
Methods: We performed immunostaining of ADAR1, an RNA-editing enzyme, in 139 cases of ulcerative colitis. In addition, normal colorectal tissue, UC inflammatory phase, normal rectal mucosa of UC carcinoma cases, and UC carcinoma sites were submitted to RNA-Seq testing in 6 cases each (24 cases total). Bioinformatics analysis was performed to compare RNA editing sites in each group.
Results: RNA-seq analysis showed a significant increase in global RNA editing sites in the inflammatory phase compared to normal colon tissue (p = 0.02). This phenomenon was due to increased ADAR1 expression associated with type 1 interferon. We hypothesized that global RNA editing was decreased in normal colonic mucosa during the remission phase but that some sites of prolonged RNA editing might promote carcinogenesis. We attempted to identify carcinogenesis-specific RNA editing sites. We identified 72 cancer-specific RNA editing sites, mainly in long noncoding RNAs such as NEAT1 and in the 3'UTR region of mRNAs such as CTSS. Assuming that the accumulation of these RNA editing leads to carcinogenesis, pathway analysis revealed that pathways promoting cancer invasion and stemness are activated. When ROC curves were generated using these editing sites as markers, the AUC was 0.935, suggesting that analysis of RNA editing in the colonic mucosa of UC patients may be able to predict the risk of carcinogenesis.
Conclusions: We identified potential editing sites for carcinogenesis in UC, allowing the identification of carcinogenic mechanisms in UC and the establishment of predictive markers for carcinogenic risk.
Citation Format: Toshiaki Takahashi, Kunitoshi Shigeyasu, Yoshitaka Kondo, Hibiki Umeda, Kazuya Moriwake, Masashi Kayano, Kaori Nitta, Fuminori Teraishi, Yuzo Umeda, Hiroshi Tazawa, Toshiyoshi Fujiwara. Establishment of predictive biomarkers for carcinogenesis in ulcerative colitis using RNA editing analyses [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB360.
Abstract LB361: The exonuclease TREX1 constitutes an innate immune checkpoint limiting cGAS/STING-mediated anti-tumor immunity
Authors: Lim Junghyun , Rodriguez Ryan , Williams Katherine , Silva John , Gutierrez Alan , Tyler Paul , Baharom Faezzah , Sun Tao , Lin Eva , Martin Scott , Kayser Brandon , Johnston Robert J. , Mellman Ira , Delamarre Lélia , West Nathaniel , Müller Sören , Qu Yan , Heger Klaus 
Published: April 2024

Abstract
The DNA exonuclease TREX1 (Three-prime repair exonuclease 1) is critical for preventing autoimmunity in mice and humans by degrading endogenous cytosolic DNA, which otherwise triggers activation of the innate cGAS/STING pathway leading to the production of type I IFNs. Since tumor cells are prone to aberrant cytosolic DNA accumulation, we hypothesized that they are critically dependent on TREX1 activity to limit their immunogenicity. Here we show, that in tumor cells TREX1 indeed restricts the spontaneous activation of the cGAS/STING pathway and the subsequent induction of a type I IFN response. As a result, TREX1 deficiency compromised in vivo tumor growth in mice. This delay depended on a functional immune system, systemic type I IFN signaling, and tumor-intrinsic cGAS expression. Mechanistically, we show that tumor TREX1 loss drove activation of CD8 T cells and NK cells, prevented CD8 T cell exhaustion and remodeled an immunosuppressive myeloid compartment. Consequently, TREX1 deficiency synergized with T cell directed immune checkpoint blockade. Collectively, we conclude that TREX1 is essential to limit tumor immunogenicity, and that targeting this innate immune checkpoint remodels the tumor microenvironment and enhances anti-tumor immunity by itself and in combination with T cell-targeted therapies.
Citation Format: Junghyun Lim, Ryan Rodriguez, Katherine Williams, John Silva, Alan Gutierrez, Paul Tyler, Faezzah Baharom, Tao Sun, Eva Lin, Scott Martin, Brandon Kayser, Robert J. Johnston, Ira Mellman, Lélia Delamarre, Nathaniel West, Sören Müller, Yan Qu, Klaus Heger. The exonuclease TREX1 constitutes an innate immune checkpoint limiting cGAS/STING-mediated anti-tumor immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB361.
Abstract LB362: Systematic development and characterization of orthotopic animal tumor models: A proactive approach to mimic patients' tumor microenvironments for drug discovery
Authors: Yang WenQing , Yuan Xusheng , Yang Guangliang , Tong Xiaojun , Ding Weiqun , Zhang Qiuxia , Lu Feng , Yang Zhijian 
Published: April 2024

Abstract
Preclinical in vivo tumor models are crucial in translational research and the pharmaceutical industry, particularly for evaluating novel anti-cancer agents. While animal tumor models are widely used in both drug development and academic research, the majority of investigations have relied on subcutaneous (SC) transplantable tumor models. These models often fail to consider the orthotopic organ origin or the unique microenvironmental differences, leading to significant limitations. Despite many publications highlighting the advantages of orthotopic tumor models (ORTH) over SC models, there is a lack of systematic analysis and comparative characterization of these formats. In this study, we have systematically developed a comprehensive ORTH tumor model platform comprising over 80 orthotopic tumor models and covering more than 25 tumor types. ORTH tumor models have been enhanced for non-invasive monitoring and increased sensitivity of tumor growth and metastasis detection through labeling with multimodality imaging markers such as GFP, RFP, and bioluminescence or imaging with micro-CT or ultrasound. We optimized and streamlined technical procedures, throughput, and reproducibility of ORTH model development, facilitating the use of these models to assess anticancer agents in a large-scale format. To mimic the clinical situation, our characterization of these models includes growth profiles, metastatic features, and survival status. Additionally, ORTH models were compared with SC models regarding the efficacy of standard-of-care (SOC) drugs through side-by-side comparison studies. As expected, inconsistent responses to SOC therapeutics were observed in some models when comparing ORTH versus SC tumors. For models yielding inconsistent results, molecular analysis and model selection recommendations will be discussed. To date, this is the first study describing the generation of a considerably large orthotopic tumor model collection and conducting a comprehensive side-by-side characterization of ORTH and SC models. This proactive approach aims to improve the mimicry of patients' tumor microenvironments and enhance the clinical relevance and potentially increase the efficiency of translational research processes.
Citation Format: WenQing Yang, Xusheng Yuan, Guangliang Yang, Xiaojun Tong, Weiqun Ding, Qiuxia Zhang, Feng Lu, Zhijian Yang. Systematic development and characterization of orthotopic animal tumor models: A proactive approach to mimic patients' tumor microenvironments for drug discovery [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB362.