bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 112: The NSG-Flt3KO; Tg(hFLT3LG); hIL15 mouse strain improves engraftment of innate immune cells post-CD34+ humanization
Authors: Boreddy Srinivas Reddy , Hu Shuang , Soper Brian 
Published: March 2024

Abstract
Human immune system mouse models play critical roles in numerous preclinical drug development pipelines, including immunology, infectious diseases, and immuno-oncology. These models are constantly evolving, with addition of human cytokines to sustain engraftment of human immune cells. To date, most humanized models have primarily focused on T lymphocyte cell biology, leaving room for improvement in developing models that effectively represent NK cells and the myeloid lineage. Previously, we demonstrated that the introduction of human IL-15 (NSG-IL-15) or FLT3L (NSG-FLT3L) to NOD-scid IL2rγnull (NSG) mice enhanced engraftment of innate immune cells, including human CD56+ NK cells, CD141+ and CD1c+ DC subsets, CD123+ pDCs, and CD14+ monocytes. In this study, we describe a new NSG mouse variant (NSG-Flt3KO; Tg(hFLT3LG); hIL15) that expresses physiological levels of both human IL-15 and FLT3L and detail the immune cell diversity following HSC engraftment. NSG-Flt3KO; Tg(hFLT3LG); hIL15 mice, along with control strains NSG, NSG-IL15, and NSG-FLT3L, were engrafted with human umbilical cord blood derived CD34+ hematopoietic stem cells from three different donors, and blood samples were collected until Week 20 post-transplantation. Blood samples were analyzed via flow cytometry to assess the engraftment of innate and adaptive immune cells. Spleen and bone marrow samples were collected at Week 12 post-transplantation and analyzed for lymphoid and myeloid immune cell populations via flow cytometry. To compare the differences among the strains in terms of immune cell sub-populations across weeks, a Two-Way ANOVA (mixed-model) was conducted, with p&lt;0.05 considered statistically significant. Overall, the results demonstrate that NSG-Flt3KO; Tg(hFLT3LG); hIL15 mice have enhanced CD56+/dim CD16+ NK cells compared to NSG-FTL3L strain (20.5±12.8% vs 7.0±3.5% at Week 12), but comparable to NSG-IL15. Furthermore, myeloid sub-lineage cells in NSG-IL15-FLT3L mice, such as monocytes, macrophages (M1), granulocytes, dendritic cells, and neutrophils, were greater than in NSG or NSG-IL15 strains, but comparable to NSG-FLT3L mice. Overall levels of hCD45+ and T cell sub-populations (CD3+ or CD4+ or CD8+) were comparable across all strains tested. In sum, our NSG-Flt3KO; Tg(hFLT3LG); hIL15 engraftment data suggest an improved model that supports drug development targeting human myeloid and NK cell populations.
Citation Format: Srinivas Reddy Boreddy, Shuang Hu, Brian Soper. The NSG-Flt3KO; Tg(hFLT3LG); hIL15 mouse strain improves engraftment of innate immune cells post-CD34+ humanization [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 112.
Abstract 1121: Targeting the DNA damage response in high-risk medulloblastoma
Authors: DeCarlo Alexandria , da Silva Carolina Fernandes , Shen Lily , Ramaswamy Vijay , Tabori Uri 
Published: March 2024

Abstract
Medulloblastoma (MB) is the most common malignant pediatric brain tumour and is currently treated with surgery, external beam radiation and chemotherapy however, current treatments are woefully inadequate, with survival of only 50% but morbidity approaching 100%. A very-high risk group of SHH-activated MB harboring TP53 mutations (TP53mut-SHH) account for a substantial proportion of treatment failures after radiotherapy with a uniformly fatal outcome. Through optimizing radiation as a selection pressure and employing a functional genetic approach through whole-genome CrisprCas-9 dropout screening, the present study aims to identify drivers of radiation resistance and uncover unique vulnerabilities to sensitize these tumours to therapy. The dropout screen was conducted across a panel of established in vitro models of sporadic murine TP53mut-SHH, which resemble the human disease with profound radio-resistance. Initial results reveal that targeting the DNA damage response confer radiation sensitization. However, consistent hits across all models demonstrate non-homologous end-joining (NHEJ) as being synthetically lethal with radiation specifically in TP53mut-SHH. Genetic knockout experiments confirm genes encoding main proteins involved in NHEJ are synthetically lethal in combination with radiation. A small molecule drug screen targeting NHEJ revealed such vulnerabilities may be therapeutically exploited in TP53mut-SHH and are able sensitize these tumours to radiation. Using our unique approach of leveraging newly established models of TP53mut-SHH with a combination of functional genetic screening and small-molecule drug screening, this study highlights the genetic mechanisms of treatment resistance and reveals novel approaches for radiation sensitization. Here, we develop a novel approach to identify targets that are synthetically lethal with radiotherapy and identify multiple synthetically lethal targets at the genetic level which can be therapeutically targeted, allowing the development of new treatments to overcome current barriers.
Citation Format: Alexandria DeCarlo, Carolina Fernandes da Silva, Lily Shen, Vijay Ramaswamy, Uri Tabori. Targeting the DNA damage response in high-risk medulloblastoma [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 1121.
Abstract 1157: Molecular signatures associated with the progression from DCIS to IDC
Authors: Chen Siqi , Karpova Alla , Lal Preet , Storrs Erik , Jayasinghe Reyka , Iglesia Michael , Houston Andrew , Zhao Yanyan , Shinkle Andrew , Mo Chia-Kuei , Herndon John , Chen Feng , Gillanders William , Ding Li 
Published: March 2024

Abstract
Patients with ductal carcinoma in situ (DCIS) are frequently overtreated. Identifying markers that accurately predict which cases of ductal carcinoma in situ (DCIS) would progress to invasive ductal carcinoma (IDC) is crucial to personalized medicine but remains a challenge. Deciphering the process of DCIS progression at cellular, molecular and genetic levels helps identify biomarkers, allowing for better informed clinical decision-making. To study molecular signatures associated with the progression from DCIS to IDC, we collected samples from breast cancer patients with co-occurring DCIS and IDC, and performed Visium spatial transcriptomics (ST), single-nucleus RNA sequencing and multiplex imaging on these samples. We identified MGP, SLC39A6, PLAT, MLPH, AZGP1, TFF1 and TFF3 as showing significant differential expression levels in DCIS compared to IDC from ST analysis, which was confirmed with snRNA analysis. Notably, in multiplex imaging, MGP and PLAT showed consistently higher expression in DCIS compared to IDC at the protein level. Moreover, we evaluated these molecular signatures using MMTV-PyMT genetic mouse models at various breast cancer progression stages (3, 6, 12, 15, and 20 weeks) with snRNA-seq and multiplex imaging platforms. Collectively, our findings highlight the importance of identifying biomarkers at the molecular level, and provide potential predictive biomarkers for DCIS progression.
Citation Format: Siqi Chen, Alla Karpova, Preet Lal, Erik Storrs, Reyka Jayasinghe, Michael Iglesia, Andrew Houston, Yanyan Zhao, Andrew Shinkle, Chia-Kuei Mo, John Herndon, Feng Chen, William Gillanders, Li Ding. Molecular signatures associated with the progression from DCIS to IDC [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 1157.
Abstract 1190: NK cell subsets as potential correlates of antitumor immunity in HPV+ cancers
Authors: O'Hara Madison , Sastry Jagannadha 
Published: March 2024

Abstract
High-risk type human papillomaviruses (HPV) are associated with genital and oral cancers, and the incidence of head and neck squamous cell cancers is fast increasing in the USA and worldwide. Survival rates for patients with locally advanced disease are poor and variable after standard of care (SOC) chemoradiation treatment (CRT). Identifying the antitumor host immune mediators important for treatment response and designing strategies to promote them are essential for improving clinical outcome. Antitumor immunity comprises of adaptive and innate immune effectors. The immediate innate immune response by natural killer (NK) cells is a critical component for antitumor efficacy. The effector function of NK cells is modulated by various receptors via a wide array of activation or inhibitory signals. Among these receptors is HLA-DR, a recognized activation marker on CD8 T and NK cells. Literature studies refer to HLA-DR+ NK cells as pre-mNK. Preclinical data demonstrated therapeutic vaccine mediated induction of pre-mNK equivalent to contribute to tumor-free long-term survival. In our studies with clinical samples from HPV+ cancer patients, we’ve observed a dysfunctional phenotype of circulating pre-mNK when compared to healthy donors, demonstrated by flow cytometry methods. The correlates for dysfunction include increased PD-1 expression, a known inhibitory receptor, and reduced CD16, an NK receptor for Antibody Dependent Cellular Cytotoxicity (ADCC). Further, we observed circulating pre-mNK cells in HPV+ head and neck patients gain functionality post-treatment, as shown by significant increases in granzyme B and CD16, both known contributors for NK cytotoxicity. In cervical cancer patients, we had the opportunity to analyze the tumor microenvironment (TME). Interestingly, we found a significant increased frequency of cytotoxic pre-mNK cells, shown by granzyme B, in the TME that was not present in circulation. Overall, pre-mNK represent a uniquely activated immune subset for antiviral and antitumor immunity.
Citation Format: Madison O'Hara, Jagannadha Sastry. NK cell subsets as potential correlates of antitumor immunity in HPV+ cancers [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 1190.
Abstract 1220: Deep mutational scanning of EGFR reveals potential domain-specific TKI sensitivities in lung cancer and glioblastoma
Authors: Hayes Tikvah , Aquilanti Elisa , Kim Erica , Persky Nicole , Brenan Lisa , Goodale Amy , Sharpe Ted , Alan Doug , Shue Robert , Golomb Lior , Silverman Brianna , Li Yvonne , Westlake Lindsay , Piccioni Federica , Cherniack Andrew , Yang Xiaoping Yang , Root David , Hicks J. Kevin , Chi Andrew , Dietrich Jorg , Cahill Daniel , Johannessen Cory , Batchelor Tracy , Meyerson Matthew 
Published: March 2024

Abstract
The epidermal growth factor receptor, EGFR, is frequently activated in lung cancer and glioblastoma by genomic alterations including missense mutations. The different mutation spectra in these diseases are reflected in divergent responses to EGFR inhibition: significant patient benefit in lung cancer, but limited in glioblastoma. Here, we report a comprehensive mutational analysis of EGFR function. We performed saturation mutagenesis of EGFR and assessed function of ~22,500 variants in a human EGFR-dependent lung cancer cell line. This approach revealed enrichment of erlotinib-insensitive variants of known and unknown significance in the dimerization, transmembrane, and kinase domains. Multiple EGFR extracellular domain variants, lacking approved targeted therapies, were sensitive to dacomitinib. Strikingly, at least two glioblastoma patients with G598V dimerization domain mutations showed responses to dacomitinib treatment together with subsequent off-target resistance in one case. In summary, this comprehensive screen reveals novel functional EGFR variants and suggests broader clinical investigation of EGFR inhibition for cancers harboring extracellular domain mutations.
Citation Format: Tikvah Hayes, Elisa Aquilanti, Erica Kim, Nicole Persky, Lisa Brenan, Amy Goodale, Ted Sharpe, Doug Alan, Robert Shue, Lior Golomb, Brianna Silverman, Yvonne Li, Lindsay Westlake, Federica Piccioni, Andrew Cherniack, Xiaoping Yang Yang, David Root, J. Kevin Hicks, Andrew Chi, Jorg Dietrich, Daniel Cahill, Cory Johannessen, Tracy Batchelor, Matthew Meyerson. Deep mutational scanning of EGFR reveals potential domain-specific TKI sensitivities in lung cancer and glioblastoma [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 1220.
Abstract 124: Validation of humanized TL1A mice for advancing preclinical research
Authors: Li Chong , Zhang Shujin , Zhang Zhi , Feng Jia , Jin James , Du Yibo 
Published: March 2024

Abstract
TL1A, or Tumor Necrosis Factor-Like Ligand 1A, plays a pivotal role in regulating the immune system and has garnered considerable attention in the field of cancer research. Studies have shown that TL1A can impact the tumor microenvironment via inflammatory signaling, immunosuppression, and tumor growth and survival. Targeting TL1A or its downstream effects could offer new avenues for cancer treatment and immunotherapy. To this end, we generated a human TL1A knock-in (B-hTL1A) mouse model. Human TL1A gene expression in B-hTL1A mice was confirmed by RT-PCR. TL1A protein expression was not altered following TL1A humanization in B-hTL1A mice as shown by flow cytometry. Lastly, soluble human TL1A was detected in B-hTL1A mice by ELISA. Due to the purported role of TL1A in mucosal immunity, efforts to induce inflammatory bowel disease in this humanized model are currently underway. Taken together, we established a preclinical B-hTL1A mouse model for the evaluation of TL1A-targeted immunotherapy.
Citation Format: Chong Li, Shujin Zhang, Zhi Zhang, Jia Feng, James Jin, Yibo Du. Validation of humanized TL1A mice for advancing preclinical research [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 124.
Abstract 1303: Harness the power of data to improve cancer care - Understanding the complex landscape of health policies and regulations
Authors: Huang Ying , Basehore Heather , Boja Emily S. , Auvil Jaime M. Guidry 
Published: March 2024

Abstract
In the era of big data and artificial intelligence, biomedical research and healthcare have been presented with unprecedented opportunities for improving the understanding of cancer biology. In addition, the Open Science Initiative aims to shift the current paradigm of research practice towards broad sharing and public access to research findings as the norm. Big data in oncology usually includes a combination of genomic sequencing, proteomics, medical imaging, electronic health records, payor records, and other data sources from pharmaceutical research, wearables, and medical devices. While combining, linking, and analyzing data from different sources across research and healthcare enterprises is key to realizing the promise of big data and a health learning system, it poses tremendous challenges for researchers and implementers to understand the nuances of relevant policies, laws, and regulations while striving for broad, equitable, timely and responsible data sharing, as well as tackling issues in data quality, harmonization, interoperability, and security. Herein, we aim to shine a light on the ever-evolving landscape of data privacy regulations, laws, and policies that govern different touch points of a patient's journey where data are collected for research and healthcare purposes throughout the lifecycle that would impact data-sharing outcomes. We hope the illumination of a complex landscape of data governance framework to consider for many data sources will facilitate broad community engagement including data scientists and technologists, patients and advocacy groups, and policymakers to maximize open data and science while protecting patient privacy and confidentiality.
Citation Format: Ying Huang, Heather Basehore, Emily S. Boja, Jaime M. Guidry Auvil. Harness the power of data to improve cancer care - Understanding the complex landscape of health policies and regulations [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 1303.
Abstract 1397: Metabolic CRISPR-Cas9 screening identifies loss of mitochondriaGene Min triple-negative breast cancer to promote lung metastasis via immune modulation
Authors: Chou Shu-Ting , Wang Xiaoyong , Edwards Deanna N. , Chen Jin 
Published: March 2024

Abstract
Triple-negative breast cancer (TNBC) is a heterogenous breast cancer characterized by an aggressive phenotype and high risk of metastatic occurrence. Metastasis is a multifaceted process that involves metabolic reprogramming, selection, and adaptation. Although studies have shown that alterations of metabolic processes can influence TNBC phenotype and sensitivity to treatments, less is known about how changes in metabolic enzymes in the tumor cells affect crosstalk between tumor and immune cells during metastasis. Here, we performed a high-throughput CRISPR-Cas9 screening of metabolic genes in an orthotopic basal-like mammary carcinoma 4T1 mouse model to identify key metabolic enzymes in the tumor cells that are associated with TNBC lung metastasis by affecting the tumor microenvironment (TME). The CRISPR-Cas9 screening showed an enrichment of sgRNA for mitochondria Gene M in the metastasized lungs of wild-type mice but not Rag1−/− mice, indicating that loss of Gene M could modulate adaptive immune cells in the TME or distant organs to promote 4T1 lung metastasis. Further pilot experiments revealed that loss of Gene M in 4T1 cells increased murine basal-like carcinoma lung metastasis in vivo and decreased population of B cells, CD4+ T cells, M2 macrophages, monocytes, and CXCR2+ neutrophils in the metastasized lungs without affecting the growth rate of the primary tumors. Overall, our preliminary results demonstrated that Gene M deficiency in 4T1 cells affects immune cell profile and drives lung metastasis of murine basal-like carcinoma cells, but the molecular and cellular mechanisms by which loss of Gene M grant tumor cells with metastatic advantage requires further investigation.
Citation Format: Shu-Ting Chou, Xiaoyong Wang, Deanna N. Edwards, Jin Chen. Metabolic CRISPR-Cas9 screening identifies loss of mitochondriaGene Min triple-negative breast cancer to promote lung metastasis via immune modulation [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 1397.
Abstract 14: Identification of tumor-reactive T cell receptors through functional single cell interaction analyses for personalized T cell therapy
Authors: Wagner Tim Robin , Kehl Niklas , Steiger Simon , Kilian Michael , Schönfelder Bruno , Boschert Tamara , Lindner Katharina , Schmidt Patrick , Rippe Karsten , Goldschmidt Hartmut , Raab Marc-Steffen , Platten Michael , Friedrich Mirco , Eichmüller Stefan B. 
Published: March 2024

Abstract
Innovative immunotherapy approaches such as adoptive transfer of chimeric antigen receptor (CAR) T cells or tumor infiltrating lymphocytes (TILs) have shown great success in the treatment of solid tumors and hematological malignancies. Although treatment of multiple myeloma with CAR T cells can induce deep responses, relapses frequently occur due to antigen escape and limited CAR T cell persistence. TCR-engineered T cells may show prolonged persistence in vivo and could mediate sustained antitumor effects. A further benefit of TCR transgenic T cells is the ability to target intracellular antigens that are inaccessible to CAR T cells, expanding the range of potential targets for immunotherapy. In our project, we propose to identify T cell receptors (TCRs) specifically targeting autologous myeloma cells. Tumor-reactive T cells were identified using the Bruker Cellular Analysis Lightning® platform, allowing simultaneous functional analysis of up to 1500 individual T cell/target cell interactions on a chip. Reactive T cells were identified upon detection of secreted cytokines (IFNγ, TNFα, IL2) and measurement of 4-1BB (CD137) surface expression. Tumor-reactive T cells showing various cytokine secretion patterns and 4-1BB expression profiles were detected in each myeloma patient (on average 11.9 T cells out of 1243 cells tested per assay run). Individual tumor-reactive T cells have been isolated and their TCRs were sequenced. TCR sequences of tumor-reactive T cells were mapped to single-cell RNA sequencing data of T cells from the same patiens to reveal a gene expression signature of myeloma-reactive T cells. TCR genes of reactive T cells were cloned and overexpressed in autologous T cells for functional validation and analysis of tumor derived neoepitope specificity. In summary, we present a pipeline allowing identification of myeloma-recognizing T cells and recovery of bona fide tumor-reactive TCRs eligible for patient-individualized T cell therapy.
Citation Format: Tim Robin Wagner, Niklas Kehl, Simon Steiger, Michael Kilian, Bruno Schönfelder, Tamara Boschert, Katharina Lindner, Patrick Schmidt, Karsten Rippe, Hartmut Goldschmidt, Marc-Steffen Raab, Michael Platten, Mirco Friedrich, Stefan B. Eichmüller. Identification of tumor-reactive T cell receptors through functional single cell interaction analyses for personalized 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 14.