bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2634: CRISPR in vivo screen utilizing removable Cas9 system to identify epigenetic immune response modulators in antigen-sensitive mouse syngeneic models
Authors: He Yuan , Liu Yafei , Wang Xiao , Li Xianyi , Dong Wenle , Hao Tongrui , Zhu Chenyang , Zhou Wenrong , Peng Zhengang 
Published: March 2024

Abstract
The application of CRISPR-Cas9 screen in tumor immunology research has promoted the discovery of potential therapeutic targets and provided a deeper understanding of the mechanisms of immunotherapy resistance. Mouse syngeneic tumor model based CRISPR in vivo screen revealed significant features of immunotherapy by better approaching the tumor immune interaction. However, the immunogenicity of CRISPR-Cas9 has been widely observed in a variety of syngeneic models, which greatly limited for the application of CRISPR in vivo screen. Herein, we used two strategies for cancer cell gene editing, Cas9 protein electroporation and loxP-flanked Cas9 with Cre recombinase, to reduce the immunogenicity of CRISPR-Cas9 in CT26 subcutaneous and Renca orthotropic syngeneic models. Encouragingly, we found out that compared with constitutive Cas9-expressing All-In-One based cell pool models, both CT26 subcutaneous model and Renca orthotropic model showed a parental cell tumor comparable growth kinetics and immune checkpoint blockade ICB response by PD-1 antibody treatment. Further immuno-profiling of tumor immune microenvironment indicated limited changes from the parental cell model, which helped the data interpretation of in vivo screen outcome. We then performed a CRISPR in vivo screen by using a focused library against mouse epigenetic regulators in these two models and will discuss the hits from the screen in future.
Citation Format: Yuan He, Yafei Liu, Xiao Wang, Xianyi Li, Wenle Dong, Tongrui Hao, Chenyang Zhu, Wenrong Zhou, Zhengang Peng. CRISPR in vivo screen utilizing removable Cas9 system to identify epigenetic immune response modulators in antigen-sensitive mouse syngeneic models [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 2634.
Abstract 270: Dissecting the effects of p53 mutation and p53 loss on pancreatic tumor microenvironment
Authors: Chen Yang 
Published: March 2024

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a devastating malignant disease with a dismal prognosis. In the past decades, a plethora of genetically engineered mouse models (GEMMs) with autochthonous pancreatic tumor development have greatly facilitated the studies of pancreatic cancer. Commonly used GEMMs of PDAC often harbor the oncogenic KRAS driver mutation (KrasG12D), in combination with either p53 mutation by knock-in strategy (Trp53R172H) or p53 loss by conditional knockout (Trp53cKO) strategy, in pancreatic cell lineages. However, the systematic comparison of the tumor microenvironment between KrasG12D; Trp53R172H (KPmut) mouse models and KrasG12D; Trp53cKO (KPloss) mouse models is still lacking. In this study, we conducted cross-dataset single-cell RNA-sequencing (scRNA-seq) analyses to compare the pancreatic tumor microenvironment from KPmut mouse models and KPloss mouse models, especially focusing on the cell compositions and transcriptomic phenotypes of major cell types including cancer cells, B cells, T cells, granulocytes, myeloid cells, cancer-associated fibroblasts, and endothelial cells. We identified the similarities and differences between KPmut and KPloss mouse models, revealing the effects of p53 mutation and p53 loss on oncogenic KRAS-driven pancreatic tumor progression.
Citation Format: Yang Chen. Dissecting the effects of p53 mutation and p53 loss on pancreatic tumor 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 270.
Abstract 2724: BCG020, a novel bispecific antibody targeting EGFR and CD70, is effective against EGFR and CD70 high expressed tumors
Authors: Yang Yongfei , Sun Xiaoxia , Li Ziyan , Yan Yue , Xu Linpeng , Wu Xiaoxue , Du Luheng , Zhu Ying , Guo Chaoshe , An W. Frank 
Published: March 2024

Abstract
The epidermal growth factor receptor (EGFR) is highly expressed across a wide range of different cancers, and is a known driver of cancer growth; EGFR upregulation is frequently associated with adverse prognosis. Many patients undergoing EGFR-TKI (tyrosine kinase inhibitors) treatment will acquire resistance, which can be accompanied by increased expression of CD70 in some cancers. Simultaneous engagement of both EGFR and CD70 with a bispecific antibody (bsAb) is a potential strategy to overcome such resistance and achieve greater efficacy. To explore this strategy, we developed a novel IgG1 bsAb, BCG020, targeting EGFR and CD70. The parental EGFR antibody and CD70 antibody were developed from fully human common light chain antibody mice (RenLite®). When compared to EGFR benchmarks, the parental EGFR antibody exhibits similar affinity to both human and cynomolgus monkey EGFR, similar internalization activity in EGFR+ tumor cell lines, and superior blocking activity of EGF to EGFR in vitro. Furthermore, the EGFR parental antibody demonstrates good stability. The parental CD70 antibody exhibits high affinity to both human and monkey CD70, with superior internalization activity to benchmark antibody in CD70+ tumor cell lines, as well as superior blockade of CD70-induced signaling of CD27-Luc when compared to benchmark antibodies. When assembled into a bsAb, BCG020 exhitibs the same high affinity as both parental antibodies, with higher internalization activity than parental antibodies and benchmark antibodies. To evaluate the efficacy of BCG020 in vivo, we established cell line-derived xenograft (CDX) models in immunodeficient (B-NDG) mice. We observed that BCG020 treatment (10 mg/kg) potently inhibited growth of EGFR+CD70+ tumors. Taken together, these data indicate that BCG020 is a first-in-class bispecific antibody with potential to treat solid tumors with high expression of EGFR and CD70.
Citation Format: Yongfei Yang, Xiaoxia Sun, Ziyan Li, Yue Yan, Linpeng Xu, Xiaoxue Wu, Luheng Du, Ying Zhu, Chaoshe Guo, W. Frank An. BCG020, a novel bispecific antibody targeting EGFR and CD70, is effective against EGFR and CD70 high expressed 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 2724.
Abstract 2752: ICA1 promotes prostate cancer progression and metastasis via AR down-regulation
Authors: Wang Fuhao , He Yu , Huang Xin , Chang Ming , Zhang Xiao , Li Xiaoyi , Ye Xinyu , Lu Yi 
Published: March 2024

Abstract
Cancer metastasis, one of the main characteristics in malignancy, contributes to high mortality in cancer patients. Prostate cancer (PCa) is the most common cancer among men and the second leading cause of cancer-related death in Europe and the United States. In China, its incidence has been dramatically increased over past years. However, the mechanism of PCa progression and metastasis remains unclear. The androgen receptor (AR) has been demonstrated to play an important role in PCa progression and metastasis. We have previously established mouse models of PCa bone metastasis and PCa lung metastasis. We have obtained cell clones with bone-specific or lung-specific metastatic capability. By transcriptomic analysis of highly metastatic cell clones and their parental cells, we found a gene group including islet cell autoantigen 1 (ICA1) that are highly expressed in both metastatic cell clones. We further compared these results with RNA array data in clinical samples. Data comparison and correlation analysis showed that ICA1 was negatively correlated with AR expression. Survival analysis of PCa and lung cancer patients showed higher expression of ICA1 but with shorter overall survival. Down-regulation of ICA1 expression in highly metastatic tumor cells significantly inhibited cell growth, colony formation, migration, and invasion. ICA1 overexpression in parental RM1 cells apparently increased cell growth, migration, and metastasis. Interestingly, down-regulation of ICA1 also significantly activated AMPK/mTOR signaling pathway. These findings are anticipated to shed light on the novel pathogenic mechanism underlying PCa and propose a compelling theoretical basis for the application of ICA1 in PCa. This work supported by the NSFC projects (81972420, 81972766, 82173336), as well as grants from the Science and Technology Project of Shenzhen (JCYJ20210324104214040, JCYJ20190809161811237).Keywords: prostate cancer, metastasis, ICA1, androgen receptor
Citation Format: Fuhao Wang, Yu He, Xin Huang, Ming Chang, Xiao Zhang, Xiaoyi Li, Xinyu Ye, Yi Lu. ICA1 promotes prostate cancer progression and metastasis via AR down-regulation [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 2752.
Abstract 2798: Oral fungal infection tweaks the innate immune tumor microenvironment promoting
Authors: Li Xin , Song Na-Young , Singh Amit Kumar , Badger Jonathan , Jiang Chengfei , Zhu Feng , Tross Debra , Zhao Yongmei , Tran Bao , Hu Yinling 
Published: March 2024

Abstract
It is yet unknown how a fungus and tumor interplay impairs innate immunity, modulating tumorigenesis. Here, we found that oral infection with Cladosporium cladosporioides of mice with Ikka deficiency in epithelial stem cells enhanced STAT3-dependent oral squamous cell carcinoma (SCC) development and fungal colonization. In wild-type mice infection was cleared up, suggesting a synergic tumor-fungus loop involved in the accelerated carcinogenesis. C. cladosporioides-mediated EGFR activation stimulated intratumor STAT3-led pathways to generate an acidic oral milieu, which disrupted bacterial compositions and suppressed neutrophil’s ROS but increased Il1b expression, dampening neutrophil’s fungitoxicity and allowing oral fungal and bacterial overgrowth. In addition, fungus-induced IL-1β/IL-17A augmented STAT3 activity in SCC cells, contributing to local and distal carcinogenesis. Significantly, fungal signals were greater in human head and neck SCCs (HNSCCs) and SCC-adjacent tissues than in healthy controls and were co-localized with IL1B-expressing neutrophils in HNSCCs. These similar traits of oncogenic pathways, microbiota dysbiosis, and defective neutrophils in HNSCC patients with poor survival highlight the importance of increased fungal infection for human malignant development and therapy.
Citation Format: Xin Li, Na-Young Song, Amit Kumar Singh, Jonathan Badger, Chengfei Jiang, Feng Zhu, Debra Tross, Yongmei Zhao, Bao Tran, Yinling Hu. Oral fungal infection tweaks the innate immune tumor microenvironment promoting [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 2798.
Abstract 28: A CRISPR/Cas9 screening platform ImmuT Finder® enables in vivo T cell functional screening and identification of potent immunoregulatory targets for next-generation T cell therapy
Authors: Sun Jingwei , Jin Jiahui , Wang Jingman , Sheng Yao , Li Fei , Chen Lingyun , Tan Yongchao , Xu Zhao , Liu Yanbin , Liu Ke , Liu Yarong 
Published: March 2024

Abstract
Insufficient tumor infiltration and the presence of various immunosuppressive mechanisms in tumor microenvironment (TME) are two major challenges compromising the anti-tumor efficacy of T cell therapy post infusion. PD-1/PD-L1 blockade has been proven to benefit a portion of late-stage solid tumor patients, however KO of PD-1 may impact the long-term persistence of CAR-T cells, indicating target selection strategies for gene editing of cell therapy products may differ from antibody drugs. To discover potent and/or novel immunoregulatory targets that could maximize the function of T cell therapy, we established an in vivo CRISPR/Cas9 screening platform, ImmuT Finder®, to identify functional gene targets in primary mouse T cells. Notably, T cells carrying sgRNA library have been collected at different harvest time points post transfer based on different screening purposes; library size has been rationally designed to ensure good coverage of the whole library in harvest samples. We selected top targets from in vivo screening and quickly validated their function in primary human T cells in a 96-well array. Then, the top targets that showed significant enhancement in proliferation and function of human T cells were further selected, and their combinational effects on human peripheral T cells and TIL were tested both in vitro and in vivo. Finally, GT307 stands out as the most potent KO combination, which significantly improves serial tumor killing of TCR-T and CAR-T as well as autologous tumor cytotoxicity of TIL in vitro. Furthermore, GT307 KO TCR-T and TIL demonstrated significantly improved tumor control in mouse models than their unedited counterparts and promoted long-term persistence with low support of IL-2. In summary, these data demonstrated that our ImmuT Finder® platform enables discovery of potent and/or novel targets for the development of T cell product and supports the clinical assessment of GT307 as a next-generation T cell therapy.
Citation Format: Jingwei Sun, Jiahui Jin, Jingman Wang, Yao Sheng, Fei Li, Lingyun Chen, Yongchao Tan, Zhao Xu, Yanbin Liu, Ke Liu, Yarong Liu. A CRISPR/Cas9 screening platform ImmuT Finder® enables in vivo T cell functional screening and identification of potent immunoregulatory targets for next-generation T cell therapy [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 28.
Abstract 2800: Shotgun metagenomics of COPD-associated lung cancer tissue microbiome
Authors: Matsuoka Atsushi , Shien Kazuhiko , Tomida Shuta , Mizuno Daisuke , Ohki Masayoshi , Yoshichika Ryo , Higashihara Tomohiro , Hayashi Naohiro , Mukohara Fumiaki , Yoshikawa Mao , Suzawa Ken , Yamamoto Hiromasa , Toyooka Shinichi 
Published: March 2024

Abstract
The gut microbiome plays a crucial role in the development of multiple chronic diseases. Several solid tumors including lung cancer are also implicated in the gut microbiome in cancer initiation and progression, possibly affecting signaling pathways in the tumor microenvironment. However, the microbiome in the peripheral lung tissue is unexplored and their relationship to the lung tumor microenvironment is still unknown. Thus, to explore the relationship between the microbiome and the tumor microenvironment of lung cancer, we performed shotgun metagenomic sequencing of the lung cancer tissue, especially in lung cancer patients accompanied by chronic obstructive pulmonary disease (COPD). We confirmed the presence of a diverse microbiome in peripheral lung cancer tissue. Next, we focused on individual species. We observed significant differences in the relative abundance of several species between COPD and non-COPD patients, and cancer and non-cancer tissue. Then, we focused on the metagenomic diversity between samples. The number of species in COPD patients and cancer tissue were decreased. And the bacterial total abundance in each sample were observed similar trend. On the other hand, alpha diversity in each sample were showed different trend to them. In the analysis of beta diversity using Principal Coordinate Analysis (PCoA), clusters were formed in each group. These findings suggest that microbiome imbalance known as dysbiosis in the peripheral lung tissue may affect the tumor microenvironment resulting in cancer progression.
Citation Format: Atsushi Matsuoka, Kazuhiko Shien, Shuta Tomida, Daisuke Mizuno, Masayoshi Ohki, Ryo Yoshichika, Tomohiro Higashihara, Naohiro Hayashi, Fumiaki Mukohara, Mao Yoshikawa, Ken Suzawa, Hiromasa Yamamoto, Shinichi Toyooka. Shotgun metagenomics of COPD-associated lung cancer tissue microbiome [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 2800.
Abstract 2833: Validating cancer biomarker expression on mouse cell-derived xenograft models of human cancer
Authors: Huang Minqi , Wiggins Alyssa E. , Marroquin D , Liu Mengling , Tsai Luke 
Published: March 2024

Abstract
Background and Objective: The target antigen expression level is critical for the potency of immune therapies like ADC, mRNA-LNP, and CAR-T. Selecting an appropriate cancer model remains a challenge to the pre-clinical drug testing. HD Biosciences offers over 1000 cell lines and 150 CDX mouse models of human cancers. Furthermore, we have validated the expression of three therapeutic targets Nectin-4, Trop2, and PD-L1 in various CDX tumor tissues. This poster will highlight some recently established models as well as the antigen validation result. Our study provides a reference that guides the model selection of efficacy studies targeting Nectin-4, Trop2, or PD-L1. In addition, we offer a platform to validate the expression of target antigens in CDX mouse models covering numerous cancer types.
Method and Result: Biomarker surface expression of Nectin-4, Trop2, and PD-L1 on xenograft tumors was validated by IHC staining and FACS analysis. We highlight these models with high expression of each marker. These models are available to support further efficacy studies of anti-cancer drugs targeting the marker. We also analyzed the biomarker surface expression in vitro using cell pellets via FACS analysis to compare with the in vivo expression level. Hence, the biomarker gene expression level was confirmed by FACS. Interestingly, the result indicates biomarker expression in mouse tumor tissues is often inconsistent with in vitro cell expression. For example, the A375 CDX model on humanized immunodeficient mice is commonly used for anti-PD-1/PD-L1 drug efficacy tests. However, the surface expression of PD-L1 is only detected in the A375 tumor tissues and is undetectable in the A375 cell pellet. This finding could explain the inconsistency of in vitro and in vivo drug test results. The in vivo CDX model-based biomarker would better predict the drug’s efficacy, as the model better mimics the clinical situation of tumor burden in patients.
Conclusion: In vitro gene expression and protein expression of cell surface biomarkers may not be relevant to the in vivo tumor surface expression level, resulting in inconsistent efficacy data in vitro and in vivo. Thus, validating targeted biomarkers in vivo is crucial for choosing the best cancer tumor model with high target expression for drug efficacy validation. HD Biosciences provides validated 150 CDX models expressing Nectin-4, Trop2, and PD-L1 and have in vivo capability for target validation and drug efficacy study.
Citation Format: Minqi Huang, Alyssa E. Wiggins, D Marroquin, Mengling Liu, Luke Tsai. Validating cancer biomarker expression on mouse cell-derived xenograft models of human cancer [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 2833.
Abstract 2908: EDB+FN is an attractive therapeutic target in oncology: Insights from protein expression analysis of solid tumors
Authors: Lewandowski Sara , Diao Liyang , Quigley Alyssa , Crochiere Marsha , Pinkas Jan 
Published: March 2024

Abstract
Stroma plays a major role in the initiation, growth, survival, and drug-resistance of solid tumors, yet few therapeutics specifically target tumor-associated stroma. Extra-domain-B fibronectin (EDB+FN) is an oncofetal splice variant of fibronectin upregulated in solid tumor stroma, which is associated with tumor growth, angiogenesis, and metastases. Here we developed an immunohistochemistry (IHC) assay to assess EDB+FN protein expression in the stroma of tumor and normal tissues to characterize the potential of EDB+FN as a therapeutic target for solid tumors with high unmet need. We validated a primary detection antibody and titrated assay conditions to achieve specificity and a broad dynamic range of EDB+FN expression levels across indications, including thyroid cancer, head and neck squamous cell carcinoma, hepatocellular carcinoma, soft tissue sarcoma, pancreatic cancer, non-small cell lung cancer, ovarian cancer, and renal cancer. Considering the stroma-specific expression pattern of EDB+FN, we developed a scoring algorithm weighting both the intensity and distribution of EDB+FN expression specifically in the stroma compartment and separately in tumor cells. Using this assay and scoring approach, we screened more than 200 tumor samples from 10 solid tumor indications and found EDB+FN to be highly differentially expressed in tumor-associated stroma with little to no expression on tumor cells and trace to undetectable levels in healthy tissue. EDB+FN was expressed across the indications evaluated with a wide range of expression both within and between indications. Stromal EDB+FN expression was not correlated with stromal density, which also varied widely within and across indications. In parallel, we developed an algorithm using digital pathology to approximate pathologist scoring of stromal density and EDB+FN expression, allowing streamlined screening of preclinical samples for in vivo studies and indication selection. The disease-specific expression pattern of EDB+FN and high incidence of expression across indications make EDB+FN an ideal target for high-unmet-need solid tumors. The specificity and dynamic range of our IHC assay for detection of EDB+FN protein expression position it as a robust potential biomarker assay for EDB+FN-targeting therapeutics.
Citation Format: Sara Lewandowski, Liyang Diao, Alyssa Quigley, Marsha Crochiere, Jan Pinkas. EDB+FN is an attractive therapeutic target in oncology: Insights from protein expression analysis of solid 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 2908.