tbuckley/cabot-search huggingface dataset:
Abstract 6104: Comparative evaluation of CAR-expressing T-, NK-, NKT-cells and macrophages in an immunocompetent mouse glioma model
Authors: Payal B. Watchmaker, Ryusuke Hatae, Akane Yamamichi, Keith Kyewalabye, Kaori Okada, Su Phyu, Yitzhar Goretsky, Jeffrey Haegelin, Psalm Pineo Cavanaugh, Marco Gallus, Lan Phung, Tiffany Chen, Hayou Long, Pavlina Chuntova, David H. Raulet, Masaki Terabe, Hideho Okada
Journal: Cancer Research (2025)

Abstract While chimeric antigen receptor (CAR) T-cells are promising, there is a rapidly growing interest in developing other CAR-expressing immune cells. However, to date, no reported studies evaluated these cells side-by-side in immune-competent glioma models. We developed a novel transgenic mouse strain with all hematopoietic cells expressing EGFRvIII-targeting CAR, allowing for rigorous evaluations of CAR-NK, CAR-NKT, and CAR-macrophages compared to CAR-T-cells in a syngeneic mouse SB28-EGFRVIII glioma model. CAR-NK and CAR-NKT-cells demonstrated anti-tumor effects comparable to CAR-T-cells in vitro. A single intratumoral administration of CAR-T and CAR-NKT-cells in combination mediated superior therapeutic efficacy compared to CAR-T-cells or CAR-NKT-cells alone. A single intravenous infusion of CAR-NK-cells following lymphodepletion failed to mediate significant anti-glioma effects associated with inferior persistence to CAR-T cells. Additionally, intratumoral injection of CAR-NK-cells did not confer therapeutic benefit. Contrary to previous reports using human macrophages, CAR-macrophages did not demonstrate enhanced antigen-presentation activity against glioma cells compared to non-CAR macrophages. Intratumorally administered CAR-macrophages failed to demonstrate local persistence or anti-tumor effects in vivo. These data provide a valuable basis as to which CAR-expressing immune cells can mediate effective anti-glioma response in an immuno-competent glioma environment. Our data also suggest that a combination of CAR-T and CAR-NKT-cells may represent a promising therapeutic strategy. Citation Format: Payal B. Watchmaker, Ryusuke Hatae, Akane Yamamichi, Keith Kyewalabye, Kaori Okada, Su Phyu, Yitzhar Goretsky, Jeffrey Haegelin, Psalm Pineo Cavanaugh, Marco Gallus, Lan Phung, Tiffany Chen, Hayou Long, Pavlina Chuntova, David H. Raulet, Masaki Terabe, Hideho Okada. Comparative evaluation of CAR-expressing T-, NK-, NKT-cells and macrophages in an immunocompetent mouse glioma model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6104.
Abstract 4417: Identification of signaling and apoptotic pathway alterations in oxaliplatin resistant HCT116 colorectal cancer cells
Authors: Aliza Jafri, Sheerien Rajput, Areeb Ahmed, Azhar Hussain Rajabali, Kulsoom Ghias
Journal: Cancer Research (2025)

Abstract Background: Chemoresistance remains a significant barrier in colorectal cancer (CRC) treatment, particularly with oxaliplatin, a key first-line chemotherapy agent. This study is therefore aimed to develop an in vitro model of oxaliplatin-resistant HCT116 cells and investigate the associated morphological and molecular adaptations to identify potential dysregulated survival and apoptotic pathways that are playing a role in developing chemoresistance. Methods: HCT116 CRC cells were cultured, and resistance was induced by stepwise oxaliplatin exposure, with recovery phases between treatments. Morphological changes during resistance development were observed using phase-contrast microscopy. Flow cytometry was performed to analyze cell cycle distribution and apoptotic cell populations. Gene expression of key survival pathways, including Wnt/β-catenin, NFκB, and PI3K/Akt, was assessed using qPCR to identify molecular alterations associated with resistance. Results: Parental HCT116 cells displayed cuboidal morphology, high proliferation (Ki-67 positivity), and epithelial characteristics (moderate E-cadherin and ALDH1 expression). Resistant cells exhibited increased morphological heterogeneity, cell detachment, and features of epithelial-mesenchymal transition (EMT). Flow cytometry revealed a significant reduction in the sub-G1 population and an increase in the G2/M phase, suggesting diminished apoptosis and cell cycle dysregulation in oxaliplatin resistant HCT116 cells as compared to wild type. Gene expression analysis showed a marked upregulation of β-catenin, NFκB, and PI3K/Akt pathway components, coupled with increased expression of EMT markers (Snail, Vimentin) and drug efflux genes (ABCG2, ABCC1) in oxaliplatin resistant cells as compared to wild type HCT116 cells suggesting a role of these survival pathways and genes in induction of resistance. Conclusion: Oxaliplatin resistance in HCT116 CRC cells is characterized by morphological plasticity, altered cell cycle regulation, and activation of survival pathways, including Wnt/β-catenin, NFκB, and PI3K/Akt. These findings highlight the complexity of chemoresistance and provide a basis for identifying novel targets to enhance treatment efficacy in CRC. Citation Format: Aliza Jafri, Sheerien Rajput, Areeb Ahmed, Azhar Hussain Rajabali, Kulsoom Ghias. Identification of signaling and apoptotic pathway alterations in oxaliplatin resistant HCT116 colorectal cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4417.
Abstract 5163: Characterization of endometrial cancer xenograft humanized mouse models
Authors: Sung Wan Kang, Ji-Young Lee, Min-Seo Lee, Ok-Ju Kang, Yong-Man Kim, Chong Jai Kim, Shin-Wha Lee
Journal: Cancer Research (2025)

Abstract Background: Recently, immunotherapy with immune checkpoint inhibitors (ICIs) has shown promising efficacy in endometrial cancer (EC), particularly in patients with mismatch repair deficiency (dMMR). Preclinical models of EC are essential for evaluating the efficacy of immuno-oncology (IO) drugs and investigating strategies to enhance the antitumor responses to immunotherapy. Humanized (Hu) mouse models can contribute to a better understanding of the underlying mechanisms associated with the improved efficacy of ICIs in treating patients with EC. Methods: We established EC xenograft Hu-mouse models by subcutaneously transplanting dMMR HEC-1A and Ishikawa human EC cells into CD34+ Hu-mice. Tumor growth was monitored by periodic measurements with a caliper. The immunophenotypical characterization of EC xenografts in Hu-mice was performed using immunohistochemical staining and flow cytometry analysis. Results: Tumor development and growth were observed in both EC cell lines within CD34+ Hu-mice. In the Hec-1A xenograft Hu-mouse model, tumor growth was significantly inhibited compared to the immunodeficient mouse model. Flow cytometry analysis of tumors, spleen, and blood from Hu-mice injected with HEC-1A cells revealed a high frequency of human immune cells, exhibiting various subtypes, including CD4+/CD8+ T cells, NK cells, NKT cells, B cells, and myeloid cells. In contrast, no significant difference in tumor growth was observed for Ishikawa xenografts between Hu- and the immunodeficient mouse model. While the spleen and blood of Hu-mice harboring Ishikawa tumors exhibited a high frequency of human immune cells similar to the HEC-1A model, the xenografts demonstrated an immune-desert phenotype, characterized by a low frequency of tumor-infiltrating immune cells. Notably, both HEC-1A and Ishikawa EC xenografts in Hu-mice exhibited a significantly higher proportion of PD-1/PD-L1+ T and B cells compared to those found in the spleen and blood. Conclusion: Two models of EC xenograft were successfully established in Hu-mice, demonstrating contrasting tumor immune phenotypes. These models might serve as valuable tools for evaluating the efficacy of immunotherapy in EC. Citation Format: Sung Wan Kang, Ji-Young Lee, Min-Seo Lee, Ok-Ju Kang, Yong-Man Kim, Chong Jai Kim, Shin-Wha Lee. Characterization of endometrial cancer xenograft humanized mouse models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5163.
Abstract 6107: Tailoring mRNA expression in T-cell therapy: advancing CAR-T functional optimization
Authors: Gilad Gibor, Shai Kilim, Neve Tzvi, Ortal Harush, Orit Itzhaki, Ronnie Shapira, Elad Jacoby, Gal Cafri, Yochai Wolf
Journal: Cancer Research (2025)

Abstract Background: T cell engineering is an emerging field in immune-oncology, and new T cell-specific modalities are required, such as gene insertion via mRNA. Cells display diverse functions and identities, requiring tailored approaches for efficient mRNA delivery. Most mRNA constructs contain standard α-globin UTRs, lacking the specificity needed for optimal T cell mRNA expression. Methods: In our study, we developed modRNA constructs by replacing the standard hemoglobin 5’-UTR with sequences derived from genes highly expressed in normal or exhausted T cells, aiming to enhance mRNA stability and protein expression. mRNA constructs containing reporter genes were electroporated into PBMC-derived T cells, with expression levels measured by flow cytometry. Results: Interestingly, we observed significant differences, with notable variability in expression arising from the replacement and directly linked to the specific gene substituted. Certain UTRs, such as Interferon gamma (IFNG), showed superior and sustained GFP expression, while others, such as TNF, exhibited reduced activity. Based on these observations, we expressed diverse CAR constructs in T cells, revealing distinct protein turnover and tonic signaling profiles. Specific constructs exhibited rapid decay, while others displayed more stable expression. These turnover patterns suggested significant differences in CAR expression levels across constructs and their impact on tonic signaling, reinforcing earlier findings on the influence of 5'-UTRs in CAR-T expression. Particularly notable were constructs that exhibited significantly lower activity and reduced expression of key activation and well-established hallmark markers of exhaustion. Cytokine secretion assays further confirmed diminished tonic signaling, especially in non-target co-cultures. Conclusions: These results underscore the critical role of T cell-specific UTRs in fine-tuning CAR-T cell activity and reducing off-target effects. Citation Format: Gilad Gibor, Shai Kilim, Neve Tzvi, Ortal Harush, Orit Itzhaki, Ronnie Shapira, Elad Jacoby, Gal Cafri, Yochai Wolf. Tailoring mRNA expression in T-cell therapy: advancing CAR-T functional optimization [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6107.
Abstract 5162: Decreases in blood pressure in a patient-derived xenograft model of pancreatic ductal adenocarcinoma
Authors: Amelia R. Malicki, Leslie M. Ogilvie, Alexa N. King, Patrick Sanosa, Jana Michaud, Bridget Coyle-Asbil, Praveen Bhoopathi, Vignesh Vudatha, Jose G. Trevino, Keith R. Brunt, Jeremy A. Simpson
Journal: Cancer Research (2025)

Abstract Introduction: Chemotherapy and radiation treatment cause cardiac injury and dysfunction. It remains unclear how cancer affects cardiac structure and function in therapy-naïve mice. Emerging data shows that epithelial ovarian cancer affects hemodynamics by causing cardiac atrophy, intrinsic cardiac dysfunction and arterial hypotension in mice. As pancreatic cancer is associated with heart disease risk, we wanted to explore if impaired hemodynamics occurs in other types of cancer. Methods: We utilized a patient-derived xenograft (PDX) model of pancreatic ductal adenocarcinoma (PDAC), established by implanting fresh tumor fragments from a human PDAC patient into NSG mice. Cardiovascular hemodynamic parameters were analyzed at 28-weeks post-tumor implantation, which coincided with an advanced stage of tumor development. Results: Invasive hemodynamic assessments showed a decrease in systolic and diastolic blood pressure. Conclusion: Independent of chemotherapy, pancreatic cancer causes arterial hypotension, impairing perfusion and overall recovery. Monitoring cardiovascular health is crucial to prevent further deterioration, optimize outcomes, and improve the quality of life for pancreatic cancer patients throughout their journey. Citation Format: Amelia R. Malicki, Leslie M. Ogilvie, Alexa N. King, Patrick Sanosa, Jana Michaud, Bridget Coyle-Asbil, Praveen Bhoopathi, Vignesh Vudatha, Jose G. Trevino, Keith R. Brunt, Jeremy A. Simpson. Decreases in blood pressure in a patient-derived xenograft model of pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5162.
Abstract 1435: ATRX loss blocks the differentiation of mesenchymal stem cells and advances undifferentiated sarcoma development
Authors: Yiming Cai, Jun Yao, Dean Pan, Yanqing Jin, James You, Wantong Yao, Haoqiang Ying
Journal: Cancer Research (2025)

Abstract Soft tissue sarcomas (STSs) are a collection of rare tumor types originated from the mesenchymal tissues. Among the over 70 histological subtypes of STS, undifferentiated sarcoma (US), which lacks any discernible morphological features of differentiated tissues, accounts for over 20% of all STSs and is correlated with high tumor grade and poor prognosis. Recent genomic profiling in US has identified p53 and ATRX among the most frequently mutated or deleted genes. ATRX is a SWI/SNF2 type of chromatin remodeling factor which functions in a histone variant H3.3-specific chaperone complex to orchestrates replication-independent nucleosome assembly at repetitive heterochromatic DNA regions including telomeres. Loss-of-function mutations occur frequently in many tumor types and is associated with the development of alternative lengthening of telomere (ALT). However, how loss of ATRX function may contribute to tumorigenesis is largely unknown. Here, we demonstrated that ATRX is required for the terminal differentiation of mouse mesenchymal stem cells (MSCs) into multiple lineages, such as adipocytes and osteocytes. Targeted deletion of Atrx in mouse MSCs, but not terminally differentiated mesenchymal lineage cells, accelerated sarcoma initiation induced by loss of p53 and significantly shortened the overall survival. Atrx-deficient tumors express high level of MSC markers such as CD44 and CD29 and exhibit pathological features highly reminiscent of human high-grade US. By analyzing the transcriptome alterations in Atrx null MSC and tumor cells, we identified a cluster of histones, highly involved in stemness maintenance, chromatin structure modifications and cell cycle, are upregulate under Atrx deletion. On the other hand, further assessment in chromatin remodeling reveals abnormal increased chromatin accessibility under Hist1/2 cluster, where most differential expressed histones are located. Transcriptomic analysis under single cell level also indicates that Atrx deficiency is associated with enhanced cell proliferation. Together, our data indicates that ATRX deficiency contributes to undifferentiated sarcoma development by inhibiting mesenchymal stem cell differentiation. Citation Format: Yiming Cai, Jun Yao, Dean Pan, Yanqing Jin, James You, Wantong Yao, Haoqiang Ying. ATRX loss blocks the differentiation of mesenchymal stem cells and advances undifferentiated sarcoma development [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1435.
Abstract 1471: Roles of the KU70 C-terminus SAP domain in resilience to ionizing radiation
Authors: Yuan Wang, Michael S. Czap, Hailey Kim, Huimei Lu, Jingmei Liu, Zhiyuan Shen
Journal: Cancer Research (2025)

Abstract Ionizing radiation (IR) is a critical modality in cancer therapy but also carries carcinogenic risks, necessitating precise optimization. The KU70 protein is integral to DNA repair, primarily known for its N-terminal domain's role in dimerizing with KU80 to repair DNA double-strand breaks (DSBs). Our study aims to elucidate the function of the less-explored C-terminal SAP domain of KU70. We engineered a variant, KU70-∆SAP, lacking this domain, to assess its role in cellular responses to radiation. KU70-∆SAP mice exhibited increased sensitivity to an 8 Gy dose of whole-body irradiation (TBI), significantly affecting hematopoietic stem cells, with marked reductions in long-term and short-term stem cells, as well as in common myeloid and granulocyte-monocyte progenitors post-irradiation. These findings suggest that the SAP domain is crucial for the survival of hematopoietic stem and progenitor populations following IR-induced damage, as well as for the subsequent hematopoiesis necessary to replenish bone marrow and blood. Further analysis using mouse embryonic fibroblast (MEF) clones from our mouse model indicated that deletion of the SAP domain impaired KU70's early recruitment to UV-laser-induced DSB sites, coinciding with decreased Ligase IV levels, an essential enzyme for DNA repair, and increased γH2AX signals, which indicate DNA damage and repair inefficiency. These results highlight the SAP domain's essential role in orchestrating effective DNA repair mechanisms post-IR and enhance our understanding of KU70’s function in improving radiation therapy outcomes and bolstering cellular resilience against radiation-induced damage. Citation Format: Yuan Wang, Michael S. Czap, Hailey Kim, Huimei Lu, Jingmei Liu, Zhiyuan Shen. Roles of the KU70 C-terminus SAP domain in resilience to ionizing radiation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1471.
Abstract 5161: Preclinical evaluation of CD3/DLL3 bispecific antibody in syngeneic and humanized mouse models for solid tumor treatment
Authors: Ravneet Chhabra, Chong Li, Shuangshi Liu, Qiang Liu, Liu Yang, Hui Xu
Journal: Cancer Research (2025)

In solid tumors, the number of T cells is limited, and immunosuppressive cells in the tumor microenvironment, such as cancer-associated fibroblasts (CAFs), myeloid-derived suppressor cells (MDSCs), and regulatory T cells (Tregs), can inhibit T cell activity. Additionally, T cells in solid tumors often exist in a state of exhaustion, reducing the effectiveness of treatments. Delta-like 3 (DLL3) is abnormally highly expressed in various tumor cell lines and primary tumor tissues, particularly showing a significant increase in neuroendocrine tumors (NETs) and small cell lung cancer (SCLC). In SCLC, the expression of DLL3 is closely associated with poor prognosis in patients. Tarlatamab is the first approved bispecific T cell engager (BiTE) therapy for the treatment of solid tumors and is the bispecific antibody (BsAb) that targets DLL3. This BiTE works by directing T cells to the vicinity of small cell lung cancer cells and activating them to eliminate tumor cells. While the powerful therapeutic effects of Tarlatamab are being highlighted, there is also a consideration for more effective assessment of bispecific antibodies. Appropriate preclinical evaluation models can provide critical data support for subsequent clinical trials of CD3/DLL3 bispecific antibodies, aiding in the understanding of their potential and mechanisms in therapy. Biocytogen successfully developed a cell line B-hDLL3 B16-F10 that expresses human DLL3. B-hDLL3 B16-F10 cell line can bind to CD3/DLL3 BsAb Tarlatamab analog (in house) and is capable of forming tumors in C57BL/6 mice and B-hCD3E/hCD28 mice after injected. When B-hDLL3 B16-F10 cells are subcutaneously implanted in B-hCD3EDG mice, the Tarlatamab analog (in house) significantly inhibits tumor growth. In PBMC-reconstituted B-NDG mice implanted with human tumor cell line SHP-77, Tarlatamab analog (in house) almost completely suppresses tumor growth. These results indicate that both preclinical animal models can be used to evaluate the in vivo efficacy of the CD3/DLL3 BsAb treatment. Citation Format: Ravneet Chhabra, Chong Li, Shuangshi Liu, Qiang Liu, Liu Yang, Hui Xu. Preclinical evaluation of CD3/DLL3 bispecific antibody in syngeneic and humanized mouse models for solid tumor treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5161.
Abstract 1433: Roles of noncoding RNAs in tumor dormancy of breast cancer recurrence
Authors: Noriko Saitoh, Maierdan Palihati, Hiroaki Tachiwana, Tomoko Fujita
Journal: Cancer Research (2025)

Abstract The vast majority of nuclear long non-coding RNAs (lncRNAs) are expressed in a cell type- or disease-specific manner. They often function as epigenetic factors, and are involved in higher-order chromatin structure [1-3]. Dysregulation of lncRNAs sometimes results in diseases, but the detailed mechanisms remain to be investigated.We have identified ELEANORS (ESR1 locus enhancing and activating non-coding RNAs), a cluster of lncRNAs in a model of endocrine therapy-resistant estrogen receptor (ER)-positive breast cancer, the LTED (long-term estrogen deprivation) cells [4]. ELEANORS are transcribed from a large chromatin domain including the gene encoding ER, ESR1. They associate with chromatin, and form a molecular condensate, the ELEANOR cloud, which is required for ESR1 gene activation. C-technologies, including Hi-C, revealed that ELEANORS define a chromatin domain, TAD (topologically associating domain) of about 0.7 Mb [5]. They also equilibrate cell growth and apoptosis by mediating a long-range chromatin interaction between the ESR1 and FOXO3 genes. The active transcription of the ESR1 locus with ELEANORS may represent frequent RNA polymerase II loading to the locus by a novel transcription initiation mechanism.Analysis of clinicopathological features of ELEANORS using patient tissues revealed that ELEANOR expression in primary tumors positively correlates with late recurrence [6]. Further, cancer stem cell populations that are involved in tumor dormancy for late recurrence were increased in LTED cells. They were decreased upon the ELEANOR knockdown, and the transcription level of the CD44 gene, a stem cell marker, also decreased. The ELEANOR and CD44 genes were frequently co-localized in the LTED cells. Thus, ELEANORS may be involved in stem cell maintenance through chromatin interactions. Our results suggest that nuclear lncRNAs are involved in 3D genome structure and pathological mechanisms. Citation Format: Noriko Saitoh, Maierdan Palihati, Hiroaki Tachiwana, Tomoko Fujita. Roles of noncoding RNAs in tumor dormancy of breast cancer recurrence [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1433.