bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2698: TCF-1 is a critical regulator of intraepithelial lymphocytes in colorectal carcinoma
Authors: Yakou Marina H. , Ghilas Sonia , Tran Kelly , Liao Yang , Afshar-Sterle Shoukat , Kumari Anita , Schmid Kevin , Dijkstra Christine , Inguanti Chantelle , Ostrouska Simone , Wilcox Jordan , Smith Maxine , Parathan Pavitha , Allam Amr , Xue Hai-Hui , Belz Gabrielle T. , Mariadason John M. , Behren Andreas , Drummond Grant R. , Ruscher Roland , Williams David S. , Pal Bhupinder , Shi Wei , Ernst Matthias , Raghu Dinesh , Mielke Lisa A. 
Published: March 2024

Abstract
Tissue-resident immune cells reside within the gastrointestinal tract known as intraepithelial lymphocytes (T-IELs), including αβ and γδ T-IELs. This unique population of T cells constantly survey and are critical in maintaining the gastrointestinal epithelium. We show that T-IELs in various regions of the gastrointestinal tract have distinct features. T-IELs in the small intestine exhibit high expression of cytotoxic molecules important for cancer defense while colon T-IELs are distinctively regulated by the transcription factor, TCF-7/TCF-1, which suppresses their effector and cytotoxic properties, including reduced expression of granzymes, and their abundance is dependent on the microbiome. Targeted deletion of TCF-1 in γδ T-IELs using pre-clinical mouse models resulted in a distinct effector profile and reduced colon tumor burden. Furthermore, TCF-1 expression was significantly reduced in γδ T-IELs present in human colorectal cancers compared with normal healthy colon, strongly correlating with an enhanced γδ T-IEL effector phenotype and improved patient survival. Further investigation aims to elucidate diverse mechanisms by which TCF-1 controls tissue-specific anti-tumor immunity and uncover the important factors controlling TCF-1 expression. Our study underscores the necessity to consider tumor and organ microenvironment-specific factors in optimizing immunotherapy, advancing our understanding of T cell function in the colon to pave the way for innovative CRC treatments.
Citation Format: Marina H. Yakou, Sonia Ghilas, Kelly Tran, Yang Liao, Shoukat Afshar-Sterle, Anita Kumari, Kevin Schmid, Christine Dijkstra, Chantelle Inguanti, Simone Ostrouska, Jordan Wilcox, Maxine Smith, Pavitha Parathan, Amr Allam, Hai-Hui Xue, Gabrielle T. Belz, John M. Mariadason, Andreas Behren, Grant R. Drummond, Roland Ruscher, David S. Williams, Bhupinder Pal, Wei Shi, Matthias Ernst, Dinesh Raghu, Lisa A. Mielke. TCF-1 is a critical regulator of intraepithelial lymphocytes in colorectal carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2698.
Abstract 2700: Therapeutic IL-33 enhances the antigen presentation function of ILC2s to exert anti-tumor immune activity
Authors: Liu Jie , Feng Zhenchu , Wei Hongyan , Li Chang , Li Xiaoshi , Chen Wenlong , Ke Yixi , Wang Minjun , Liu Lantian , Zheng Cunni , Liu Quan 
Published: March 2024

Abstract
IL-33 regulates the function of ILC2s through ST2. However, the role of IL-33, especially exogenous IL-33, on ILC2s in tumors is controversial depending on the cytokines they secrete. Here we report that exogenous, but not endogenous, IL-33 significantly inhibits the progression of a variety of mouse solid tumors, including melanoma, colorectal cancer, lung adenoma, and breast cancer. By inoculating tumor cells in Il1rl1−/- and NSG mice, we found that the tumor-suppressive effect of IL-33 on tumors was dependent on the expression of ST2 receptors and the presence of lymphocytes. Regarding tumor-infiltrating immune cells, exogenous IL-33 significantly increases the proportions of ST2+ Tregs (1.10 ± 0.20% vs. 1.74 ± 0.36%), eosinophils (6.00 ± 1.33% vs. 22.73 ± 6.51%), Granzyme B+ CD8+ T cells (4.32 ± 2.77% vs. 11.53 ± 6.81%), and bulk ILC2s (0.08 ± 0.04% vs. 5.31 ± 1.33%) and IA/IE+ ILC2s (0.02 ± 0.01% vs. 3.67 ± 1.03%). In draining lymph nodes, IL-33 also significantly increases the proportions of ILC2s (0.03 ± 0.02‰ vs. 6.37 ± 1.71‰) and IA/IE+ ILC2s (0.003 ± 0.003‰ vs. 4.38 ± 1.21‰). Importantly, single-cell transcriptomic analysis on tumor-infiltrating ILC2s highlights the expression of genes related with antigen processing and presentation including H2-K1, H2-Q7, B2m, Hspa1a, Hspa1b, Creb1, Hspa4, Tap1 and Tap2. We testified this finding by DQ-OVA experiment and found that IL-33 could promote ILC2s to up-take and process exogenous antigens (17.78 ± 0.75 fold vs. 22.02 ± 0.75 fold). The antigen presentation function of ILC2s was further established by mixed lymphocyte culture where BALB/c ILC2s potently stimulated C57BL/6 CD8+ T cell proliferation, which was further augmented by IL-33 treatment. Taken together, our data demonstrate an anti-tumor function of therapeutic IL-33 that elevates the number and antigen presentation function of ILC2s.
Citation Format: Jie Liu, Zhenchu Feng, Hongyan Wei, Chang Li, Xiaoshi Li, Wenlong Chen, Yixi Ke, Minjun Wang, Lantian Liu, Cunni Zheng, Quan Liu. Therapeutic IL-33 enhances the antigen presentation function of ILC2s to exert anti-tumor immune activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2700.
Abstract 2703: Targeting STING pathway as a therapeutic strategy against β-catenin driven immune escape and resistance to anti-PD1 therapy in hepatocellular carcinoma
Authors: Zhang Qingmei , Bi Jiacheng , Yeung Oscar Wai-Ho , Ding Tao , Chan Wing-Lim , Zhu Yueqin , Liu Jiang , Ng Kevin Tak-Pan , Man Kwan 
Published: March 2024

Abstract
β-catenin mutation occurs in around 40% of hepatocellular carcinoma(HCC); yet no precision therapies are available to treat this tumor subset. Immune checkpoint inhibitors (ICIs) are now widely used for the treatment of patients with advanced HCC. Unfortunately, preliminary evidence showed that β-catenin mutation drives resistance to anti-PD1 immunotherapy in HCC. In this study, we studied the molecular mechanisms underlying β-catenin mutation during HCC pathogenesis to develop novel therapeutics targeting β-Catenin-driven HCC. Firstly, three HCC cohorts were examined, including 70 untreated, 20 treated patients with nivolumab, and patients from a public TCGA database. By single-cell RNA sequencing analysis, we identified that anti-PD-1 treatment displayed effectiveness with the increase of CD27+CD8+ T-cell infiltration, correlating to improved prognosis with longer progression-free survival (PFS) and OS. Importantly, multiplex IHC staining showed that β-catenin activation is associated with significantly reduced CD8+CD27+ T cell infiltration in tumors (n=70), demonstrating that β-catenin promoted immune escape and resistance to anti-PD-1 treatment involved defective cytotoxic T-cell activity. Subsequently, we found that the interaction of β-Catenin with sirtuin 1 (SIRT1) mediated suppression of IRF3/IRF7 activity, resulting in inhibition of Type I interferon (IFN-I) production. However, by CRISPRi screening, we found that disruption of β-catenin-SIRT1 interaction via STING caused persistent high-level IFN-I response which increased the transcription of T-cell costimulatory molecule CD27 via IL10/STAT3/BATF signaling on infiltrated CD8+ T cells. This effect was also confirmed in the STING null mice, emphasizing that STING signaling is a therapeutic target to overcome β-catenin driven immune escape. Further, using hydrodynamic tail-vein injection murine HCC models, we found that the STING agonist inhibited β-catenin-SIRT1 activity, restored IFN signaling to rescue T-cell cytotoxic capacities, and enhanced the anti-PD-1 therapy efficacy. In conclusion, we demonstrated that STING reprogrammed β-Catenin mutated the HCC tumor microenvironment and a combination of STING and anti-PD-1 treatment represents an effective novel therapeutic strategy for HCC patients with β-Catenin mutation.
Citation Format: Qingmei Zhang, Jiacheng Bi, Oscar Wai-Ho Yeung, Tao Ding, Wing-Lim Chan, Yueqin Zhu, Jiang Liu, Kevin Tak-Pan Ng, Kwan Man. Targeting STING pathway as a therapeutic strategy against β-catenin driven immune escape and resistance to anti-PD1 therapy in hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2703.
Abstract 2759: Transcriptional intra-tumoral heterogeneity of putative therapeutic targets in colorectal cancer peritoneal metastases
Authors: Zhao Joseph J. , Ong Johnny CA , Chia Daryl Kai Ann , Teo Melissa Ching Ching , Tan Qiu Xuan , Ng Gillian , Tan Joey Wee-Shan , Ma Haoran , Ong Xuewen , Tay Su Ting , Tan Patrick , Sundar Raghav 
Published: March 2024

Abstract
Background: The poor prognosis of peritoneal metastasis (PM) in colorectal cancer (CRC) is typically attributed to, and characterized by, resistance to systemic chemotherapy and immunotherapy. The evolutionarily conserved plasma-peritoneal barrier as well as reduced tumor tissue vascularity contributes to poorer responses to systemically administered antineoplastic therapy. Beyond these, we sought to understand transcriptomic variations of important therapeutic targets implicated in peritoneal organotropism and by extension, resistance to systemic regimens in CRC PM.
Methodology: FFPE tissue samples from CRC patients were collected during oncological surgical resection of the synchronous PM (cytoreductive surgery [CRS] with or without hyperthermic intra-peritoneal chemotherapy [HIPEC]), or exploratory laparotomy for palliative surgery, with the majority of patients receiving systemic therapy prior to surgery. Samples were sequenced with whole transcriptomic sequencing. Paired and unpaired T-tests between PT and PM samples were undertaken with log2(fragments per kilobase of exon per million mapped [FPKM]) gene expression values.
Results: Fifty-six (22 primary tumor [PT], 34 peritoneal metastases [PM]) samples from 35 patients, comprising 21 paired PT-PM samples, were included in this analysis. TEAD1 (unpaired T-test, p=0.087; paired T-test, p=0.041), FGFR1 (unpaired T-test, p=0.003; paired T-test, p&lt;0.001), PIK3CA (unpaired T-test, p=0.034; paired T-test, p=0.003), SMAD4 (unpaired T-test, p=0.095; paired T-test, p=0.010), and HAVCR2 (unpaired T-test, p=0.009; paired T-test, p=0.007) were found to be upregulated in the PM. Conversely, MET was found to be downregulated in PM samples (unpaired T-test, p=0.004; paired T-test, p=0.002). There were no significant differences in gene expression profiles of BRAF, RHOA, CD274, CTLA4, PDCD1 and TIGIT between PT-PM (all p&gt;0.05).
Conclusion: Through CRC PT-PM comparisons, we identify potential therapeutic targets implicated in transcoelomic metastasis and provide rationale for development of immunotherapeutic biology and drug discovery for CRC PM. These findings underscore an exigent need to develop intra-peritoneal therapeutic strategies to overcome resistance to systemic regimens.
Citation Format: Joseph J. Zhao, Johnny CA Ong, Daryl Kai Ann Chia, Melissa Ching Ching Teo, Qiu Xuan Tan, Gillian Ng, Joey Wee-Shan Tan, Haoran Ma, Xuewen Ong, Su Ting Tay, Patrick Tan, Raghav Sundar. Transcriptional intra-tumoral heterogeneity of putative therapeutic targets in colorectal cancer peritoneal metastases [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2759.
Abstract 2802: Enterococcus faecalis-derived X facilitates pancreatic tumor by regulating immune microenvironment
Authors: Wang Bin , Yang Chao , Xie Yongjie , Zhou Tianxing , Yu Jun , Hao Jihui 
Published: March 2024

Abstract
Previous research in human samples has found a link between the intratumoral microbiome and the development and progression of pancreatic cancer. Nevertheless, the bacterial strains that may have an effect, and the underlying mechanisms, are largely unknown. To identify potential bacterial species, microbiome sequencing was performed on fecal and tumor samples obtained from KPC mice and patients with pancreatic tumors in this study. To identify metabolites associated with bacteria, untargeted metabolomics were analyzed on serum and tumor samples. Furthermore, advanced and high-throughput techniques, such as single-cell RNA sequencing, tumor organoids, engineered bacteria and germ-free mouse models, were used to elucidate the specific influence on the immune microenvironment of pancreatic tumors. Our findings reveal an increased abundance of Enterococcus faecalis (E. faecalis) in the gut during the development of pancreatic cancer, accompanied by its accumulation in the tumor. Patient-derived E. faecalis strain and its metabolite X, facilitated pancreatic tumor growth, reduced the recruitment of CD8+T cells, and caused their dysfunction in the tumor, relying heavily on E. faecalis intratumoral colonization. We found that X inhibits the production of anti-tumor chemokines like CCL21 and CCL8 in tumor cells, reducing peripheral CD8+ T cell infiltration into the tumor. Furthermore, X was found to inhibit glycolysis and compromise the function of tumor-infiltrating CD8+ T cells by decreasing the activity of lactate dehydrogenase (LDH) in CD8+ T cells. Additionally, oral doxycycline, an antibiotic that targets intratumoral E. faecalis, effectively enhanced the therapeutic effect of gemcitabine in pancreatic cancer. Finally, we present evidence that X may predicts efficacy and survival in pancreatic cancer patients. Together, our findings provide new insights into the role of E. faecalis in mediating the immune environment of pancreatic tumors, highlighting E. faecalis and X as potential therapeutic targets for pancreatic cancer patients.
Citation Format: Bin Wang, Chao Yang, Yongjie Xie, Tianxing Zhou, Jun Yu, Jihui Hao. Enterococcus faecalis-derived X facilitates pancreatic tumor by regulating immune microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2802.
Abstract 2835: Comparison of xenograft and syngeneic cancer cachexia models for preclinical drug testing
Authors: Draheim Kyle , Gietl Diana , Shinn Karyn , Durham William , Zhao Fei , Thompson Caitlin , Baldwin Alexis , Harris Glenn , Hall Chassidy , Fadden Patrick , Avrutskaya Anya 
Published: March 2024

Abstract
Cancer cachexia is a wasting syndrome characterized primarily by loss of skeletal muscle and adipose tissue mass and contributes greatly to overall cancer-related mortality (for recent review see Argiles 2023). An estimated 25-75% of cancer patients develop cachexia which leads to impacts on therapeutic tolerability, well-being, and eventually overall survival (Bossi 2021). Some preclinical mouse and rat cancer models manifest cachexia as they progress. In this study we established a syngeneic (immune competent) and a xenograft (immune incompetent) tumor model of cachexia with the intention of comparing the models with respect to typical study endpoints and to provide a platform for testing novel therapeutic agents aimed at inhibiting or reversing the effects of cachexia. The Colon26 syngeneic mouse colon adenocarcinoma model was reported as an experimental cancer cachexia model by Tanaka, et. al. in 1990. The model was developed in male BALB/c × DBA/2 F1 (first generation cross) mice. We typically implant Colon26 in female BALB/c mice for preclinical drug testing of anticancer agents and noticed a strong tendency for mice bearing Colon26 tumors to develop signs of cachexia on study, but not always consistently. A review of the literature showed there are clear gender differences with male cancer patients having higher prevalence of cachexia and greater muscle loss compared with female patients (Zhong 2020). Based on this we implanted Colon26 tumors in male BALB/c mice to establish the cachexia model. The HT1080 human fibrosarcoma model HT1080 was characterized as a cachexic model by Bernardo, et. al. in female severe combined immunodeficiency disease (SCID) mice. We developed the HT1080 model in male SCID mice based on the literature and previous experience. Both models were characterized by multiple endpoints including overall body weight loss, skeletal muscle weight loss, reduction of adipose tissue, and cardiac muscle loss, as well as tracking a broad panel of relevant cytokine levels at study endpoint. Both models generate robust wasting of skeletal muscle and adipose tissue providing an opportunity to assess novel anti-cachexia therapies.
Citation Format: Kyle Draheim, Diana Gietl, Karyn Shinn, William Durham, Fei Zhao, Caitlin Thompson, Alexis Baldwin, Glenn Harris, Chassidy Hall, Patrick Fadden, Anya Avrutskaya. Comparison of xenograft and syngeneic cancer cachexia models for preclinical drug testing [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2835.
Abstract 2851: Characterization of neogenes in desmoplastic small round cell tumors
Authors: Truong Danh , Magrath Justin , Lee Sean , Ludwig Joseph 
Published: March 2024

Abstract
Desmoplastic Small Round Cell Tumor (DSRCT) is a rare, soft tissue sarcoma caused by the EWS::WT1 fusion protein (FP). The FP acts as an aberrant transcription factor with oncogenic properties. Recently, oncogenic chimeric transcription factors (OCTF), such as EWS::WT1, were discovered to induce the expression of novel transcripts in otherwise silent genomic regions. These neogenes (NGs) are highly specific to each OCTF and not detected in normal tissue. 37 NGs were found to be associated with the EWS::WT1 FP.We explored the NGs to characterize their expression and regulation in a cohort of MD Anderson Cancer Center patients. We annotated and counted the NGs from the bulk RNA-seq data of 37 specimens. After fusion detection, only 22/37 specimens harbored the EWS::WT1 FP. We found that only the same 22 specimens robustly expressed DSRCT-specific NGs. Interestingly the NGs were heterogeneously expressed, suggesting that there may be patient-specific differences. Single-nucleus RNA-sequencing (snRNA-seq) of Ewing sarcoma (ES), CIC::DUX4 sarcoma (CDS), DSRCT, and osteosarcoma revealed that only the three sarcomas driven by an OCTF robustly expressed NGs. Notably, the DSRCT-specific NGs were only expressed in DSRCT. Similarly, ES and CDS only expressed their subtype-specific NGs. Given the robust expression of the DSRCT-specific NGs in DSRCT, we asked if the EWS::WT1 FP regulated the expression of the NGs. Knockdown (KD) of the EWS::WT1 FP in four DSRCT cell lines showed a consistent reduction in DSRCT-specific NGs. While there was variability in NG expression and EWS::WT1 FP KD sensitivity, we identified seven NGs decreased by at least 75% in all four cell lines and an additional eight NGs with 75% reduction across three cell lines. BOD-DSRCT and SK-DSRCT2 had the largest number of NGs reduced after KD, with 25/37 and 20/37 NGs with 75% expression reduction, respectively. EWS::WT1 FP has two known isoforms generated by alternative splicing in the WT1 domain that includes or excludes three amino acids, lysine, threonine, and serine (KTS) between zinc fingers 3 and 4, producing E+KTS and E-KTS isoforms. By transducing one or both isoforms into the mesothelial cell line LP9, we found 3/37 NGs were induced by the E+KTS isoform and 17/37 were induced by the E-KTS isoform, suggesting that the E-KTS isoform is primarily responsible for NG expression. Current work is underway investigating the relationship between EWS::WT1 FP binding and NG expression and the potential for NG to produce novel peptides that could serve as DSRCT immunotherapy targets.
Citation Format: Danh Truong, Justin Magrath, Sean Lee, Joseph Ludwig. Characterization of neogenes in desmoplastic small round cell tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2851.
Abstract 2949: A flexible and efficient approach for single-cell CRISPR perturbation screens combined with targeted RNA-seq expression analysis
Authors: Tedesco Donato , Liu Tianbing , Makhanov Mikhail , Hu Dongfang , Isachenko Nadya , Diehl Paul , Chenchik Alex 
Published: March 2024

Abstract
This study presents a novel approach for performing 10X platform-based targeted single-cell RNA-seq analysis in combination with CRISPR perturbation screens. For the analysis, we constructed a custom sgRNA library focused on a small subset of genes associated with the TNFα response (i.e., NFκB pathway). We compared analysis of two targeted gene expression panels—the first, targeting all protein-coding genes (genome-wide) and the other, targeting a selected set of genes representing key hubs in signaling pathway modules. Narrowing down the analyzed gene set enhanced the efficiency of single-cell RNA-seq by reducing the associated next-generation sequencing (NGS) depth required for readout, and significantly streamlining data analysis. Comparing the analysis of the expression panels targeting all protein-coding genes with the smaller pathway-targeted set, we were able to assess the general flexibility of the novel approach for single-cell CRISPR perturbation screens. We evaluated the specific tradeoffs with regard to the size of the CRISPR library, the size of the panel of genes targeted for expression analysis, and NGS sequencing depth. This flexible, targeted approach not only refines the precision of RNA-seq but also provides a more cost-effective solution for comprehensive genomic analyses.
Citation Format: Donato Tedesco, Tianbing Liu, Mikhail Makhanov, Dongfang Hu, Nadya Isachenko, Paul Diehl, Alex Chenchik. A flexible and efficient approach for single-cell CRISPR perturbation screens combined with targeted RNA-seq expression analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2949.