bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3960: Establishment of humanized mouse models engrafted with luciferase-expressing acute myeloid leukemia cell lines
Authors: Bayon Emilie , Mersni Arije , Wetzel Audrey , Villé Jade , Yin Kiave Yune Ho Wang 
Published: March 2024

Abstract
Introduction: Because acute myeloid leukemia (AML) is a very aggressive and quickly developing cancer, for which actual treatments are either inefficient, poorly tolerated, or leading to resistance, there is a strong need for an effective platform to evaluate novel therapies. Our aim is to provide a relevant humanized mouse model as a precious tool to evaluate innovated treatments to cure AML.
Methods: Mice were humanized with CD34+ hematopoietic stem cells to reconstitute a complete human immune system. Three AML cell lines, namely OCI-AML2, OCI-AML3 and MOLM-14, all expressing mCherry and luciferase, were intravenously engrafted at different doses in non-humanized and CD34-humanized mice. Tumor proliferation was monitored by bioluminescence imaging (BLI) thanks to luciferase expression on tumor cells. Their expression of mCherry was also exploited to determine the presence of tumor cells in blood and tissues using flow cytometry.
Results: All AML cell lines engrafted in mice, but we observed different growth kinetics and homogeneity depending on the humanization of mice and the dose injected. Indeed, tumor grew more slowly and heterogeneously in humanized mice, which underlines the role of human immune cells reconstituted in mice. This was improved by increasing the number of tumor cells injected. Tumor cells were found in femurs, spleen, kidneys, ovary, lungs, and uterus depending on the cell line. Mice survival was also highly affected by the tumor cell line engrafted. We observed that MOLM14 was the most aggressive model, while OCI-AML3 reached a steady state and were tolerated by mice over a long period.
Conclusion: We established 3 different AML cell lines in a model of humanized mice which nicely recapitulates the growth of tumor cells in target organs. These 3 models behave differently in terms of growth kinetic, tolerability by mice, and organs infiltrated, which gives plenty of opportunities to evaluate novel therapies designed to cure AML.
Citation Format: Emilie Bayon, Arije Mersni, Audrey Wetzel, Jade Villé, Kiave Yune Ho Wang Yin. Establishment of humanized mouse models engrafted with luciferase-expressing acute myeloid leukemia cell lines [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 3960.
Abstract 3971: Progesterone impacts regulatory T cell activity to promote immunosuppression in the mammary gland
Authors: Chowanec Eilidh I. , Werner Lauryn R. , Hagan Christy R. 
Published: March 2024

Abstract
Estrogen and progesterone signaling together drive hormone-receptor positive breast cancer growth and progression. However, there have been limited studies on the independent role that progesterone and its receptor, the progesterone receptor (PR), play in the development of breast cancer. Studies in the Hagan lab have shown that progesterone signaling promotes mammary tumor growth and changes the immune landscape of the mammary gland towards immunosuppression. Regulatory T-cells (Tregs) are immune cells known to promote immunosuppression in the tumor microenvironment. The data from our lab shows that among hormone receptor positive breast cancers, higher levels of PR expression correlates to higher levels of Tregs in the tumor microenvironment. To determine if progesterone signaling increases the number of Tregs in the tumor-bearing mammary gland, we used a syngeneic orthotopic murine tumor model, E0771 cells, engineered to express mouse PR or control empty vector. Mice were treated with progesterone or placebo for 7 days before implantation of the modified E0771 cells. The results of this study show that progesterone promoted tumor growth, and flow cytometry analysis at tumor endpoint showed that PR-positive tumors treated with progesterone harbored more Tregs than mice treated with placebo. Additionally, initial studies using flow cytometry and RNA-seq indicate increased Treg activity following progesterone treatment in PR+ tumor-bearing mice. As progesterone treatment promoted tumor growth and Treg recruitment in progesterone receptor-positive tumors, these data imply that progesterone treatment may promote the release of secreted factors impacting the immune cells in the mammary microenvironment. To determine if progesterone treatment results in cytokine or chemokine changes that may affect Treg recruitment, cytokine arrays and enzyme-linked immunosorbent assays (ELISAs) were performed using cell culture supernatant from murine mammary tumor cells expressing progesterone receptor (E0771-PR) treated with progesterone (0-72 hours). E0771-PR cells treated with progesterone showed higher levels of cytokines and chemokines that have been linked to Treg recruitment and differentiation, such as MCSF. Our findings demonstrate that progesterone signaling promotes an immune suppressed microenvironment in the mammary gland through an increase in Tregs. This evidence provides rationale to investigate the use of anti-progestins as a mechanism to overcome the immune-cold tumor microenvironment seen in progesterone receptor positive breast tumors.
Citation Format: Eilidh I. Chowanec, Lauryn R. Werner, Christy R. Hagan. Progesterone impacts regulatory T cell activity to promote immunosuppression in the mammary gland [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 3971.
Abstract 3976: Single-cell TCRɑ/β and TCRγ/δ immune receptor profiling and immunophenotyping using a 96-well plate sorted-cell approach
Authors: Chenchik Alex , Liu Tianbing , Makhanov Mikhail , Hu Dongfang , Kobzik Lester , Ghias Khadija , Diehl Paul 
Published: March 2024

Abstract
Single-cell immune receptor profiling is a revolutionary approach that allows investigators to combine clonotype repertoire identification with paired-chain information and the phenotype of cells (e.g., cell subtype). Single-cell immune receptor profiling can be performed using a medium-throughput approach (1,000-5,000 cells) using microwell arrays or droplet microfluidics technologies. However, these assays are more complicated to run and require expensive reagents and limited sequencing throughput when compared to bulk immune receptor profiling methods.
Here, we describe a low-throughput, single-cell immune profiling strategy using sorted cells in 96-well plates. The plate is pre-aliquoted with either T-cell receptor (TCR) ɑ/β or TCR γ/δ primers along with 30 crucial T-cell markers. We perform multiplex RT-PCR amplification and sequencing of the CDR3 regions. The resulting data provides the abundant clonotype counts along with the chain pairing information for these ɑ/β and γ/δ chains, together with the T-cell subtype information using gene-expression profiles. By analyzing the TCR gene rearrangement at the single-cell level, researchers can better understand T cell development, proliferation, and clonality, which are crucial for studying diseases such as cancer, immunodeficiency, and autoimmunity. Furthermore, single-cell TCR sequencing when combined with RNA sequencing datasets, facilitates the identification of γδ T cells. This method provides a standardized tool for identifying potential γδ T cell-based cancer immunotherapies. The technology's cost-effectiveness and ability to analyze clonotypes and immunophenotypes of cells in a single assay make it a valuable tool for unraveling the immune dynamics in various diseases.
Citation Format: Alex Chenchik, Tianbing Liu, Mikhail Makhanov, Dongfang Hu, Lester Kobzik, Khadija Ghias, Paul Diehl. Single-cell TCRɑ/β and TCRγ/δ immune receptor profiling and immunophenotyping using a 96-well plate sorted-cell approach [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 3976.
Abstract 4035: Lipid-based nanoparticle combination immunotherapy with sitravatinib for the systemic treatment of high-risk neuroblastoma
Authors: Diaz-Infante Miranda , Kane Griffin , Lusi Christina , Brassil Meghan , Wigglesworth Kim , Alarcon Christian , Shohet Jason , Atukorale Prabhani 
Published: March 2024

Abstract
We seek to develop a systemic, innate immunomodulatory nanoparticle therapy that combines synergistically with sitravatinib for the treatment of high-risk neuroblastoma, where metastasis is the largest hurdle for current treatment modalities. Here, we utilize a unique lipid-based nanoparticle (LNP) system comprised of co-encapsulated agonists of the Stimulator of Interferon Genes (STING) and Toll-like Receptor 4 (TLR4) pathways (immuno-NPs) that can be safely administered in the systemic blood circulation for delivery to the tumor microenvironment (TME) and uptake by perivascular innate antigen-presenting cells (APCs). STING/TLR4 agonists together promote the synergistic production of Type I interferon β (IFNβ), a key activator of anti-tumor immunity from the TME itself. Here, we also focus on sitravatinib, an investigational drug shown to inhibit receptor tyrosine kinases such as discoidin domain receptor 2 (DDR2), which can inhibit the sustained remodeling of collagen around primary tumors. The inhibition of such is vital to treatment as sustained collagen remodeling can facilitate the metastasis of cancer cells via epithelial-mesenchymal transition (EMT). We hypothesize that the downstream effects of sitravatinib treatment will augment tumor clearance and increase the therapeutic efficacy of immuno-NPs with respect to recruiting APCs. Our early pilot studies in humanized mice bearing orthotopic SH-5YSY tumors show that immuno-NPs are effective at tumor clearance. We found that mice inoculated subcutaneously with syngeneic 9464D-GD2 tumors showed decreased tumor growth when treated with our novel combination therapy in comparison to monotherapy controls. In both humanized and syngeneic tumor models, our ongoing mechanistic studies involve quantification of EMT in primary tumors, systemic nanoparticle deposition at metastatic sites, and the mechanistic impact of combination therapy on IFNβ-promoted elimination of metastasis. Here, we have proposed and tested an immunotherapy with great promise for treating neuroblastoma. However, the impact of nanoparticle-based immunotherapy reaches far beyond neuroblastoma: it has the potential to be a platform for the development of immunotherapies specific to other highly metastatic cancer types.
Citation Format: Miranda Diaz-Infante, Griffin Kane, Christina Lusi, Meghan Brassil, Kim Wigglesworth, Christian Alarcon, Jason Shohet, Prabhani Atukorale. Lipid-based nanoparticle combination immunotherapy with sitravatinib for the systemic treatment of high-risk neuroblastoma [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 4035.
Abstract 4037: Optimizing the efficacy of anti-VEGF/cytotoxics/anti-PD-1 scheduling in a lung cancer mice model through B and T cells monitoring
Authors: Sicard Guillaume , Protzenko Dorian , Giacometti Sarah , Fanciullino Raphaelle , Barlesi Fabrice , Ciccolini Joseph 
Published: March 2024

Abstract
The exact modalities of combinatorial regimens associating Immune Checkpoint Inhibitors (ICI) with other treatments are yet to be defined. Understanding how and when cytotoxics best reshape tumor immunity could help optimizing the scheduling of ICI’s. In vivo studies were performed on C57BL/6 mice grafted with LL/2lung cancer cells. A longitudinal immunomonitoring study on tumor, spleen and blood after multiple treatments including Cisplatin, Pemetrexed and anti-VEGF as single agents and in combination was performed for up to 21 days to determine the best time-window during which immune checkpoint inhibitors should be added. Finally, an efficacy study was conducted comparing the antiproliferative performance of various schedules of anti-VEGF, Pemetrexed-Cisplatin doublet, plus anti-PD-1 (i.e., immunomonitoring-guided scheduling, concurrent dosing or a random sequence). Immunomonitoring showed marked differences between treatments, organs and time-points. However, harnessing tumor immunity (i.e., promoting CD8 lymphocytes or increasing the CD8/Treg ratio) started on D7 and peaked on D14 with the anti-VEGF followed by cytotoxics combination. Therefore, a two-week delay between anti-VEGF/cytotoxic and anti-PD1 administration was considered the best sequence to test. Efficacy studies then confirmed that this sequence achieved higher anti-proliferative efficacy compared to other treatment modalities (i.e. -71% in tumor volume compared to control at the end of the study). Anti-VEGF and cytotoxic agents show time-dependent immunomodulatory effects, suggesting that sequencing is a critical feature when combining these agents with immune checkpoint inhibitors. Our efficacy study confirmed that sequencing treatments further enhances anti-proliferative effects in lung cancer models compared to concurrent dosing.
Citation Format: Guillaume Sicard, Dorian Protzenko, Sarah Giacometti, Raphaelle Fanciullino, Fabrice Barlesi, Joseph Ciccolini. Optimizing the efficacy of anti-VEGF/cytotoxics/anti-PD-1 scheduling in a lung cancer mice model through B and T cells monitoring [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 4037.
Abstract 4047: Unraveling synergistic therapeutic strategies involving FAK inhibition and immunotherapy using anti-PD1 antibody in KRAS and LKB1-driven lung cancer
Authors: Koo Junghui , Tucker-Burden Carol , Roy Melissa , Huang Chunzi , Zhou Wei , Gilbert-Ross Melissa , Fu Haian , Ramalingam Suresh S. , Marcus Adam I. 
Published: March 2024

Abstract
Lung cancer presents a global health challenge demanding innovative preclinical models forresearch and therapeutic advancement. Genetically engineered mouse models (GEMMs) have seenremarkable growth in complexity and application over the past two decades. Our work leveragesthese models and is specifically designed to address the pressing need for effectiveimmunochemotherapies in the context of KRAS and LKB1 (KL) mutant lung adenocarcinoma,which shows resistance to most immunotherapies. Our study centers around a preclinicalsyngeneic orthotopic mouse model we developed using mouse lung and metastatic tumor cell linesderived from KL-GEMM. This model, optimized to mimic human lung cancer closely, providesan ideal platform for exploring the intricate interplay between the immune system and tumorprogression. Furthermore, we have previously shown the LKB1 mutant cell lines and tumormodels are uniquely sensitive to FAK inhibitors, and therefore we wanted to test whether thecombination of a FAK inhibitor with anti-PD1 therapy can improve sensitivity. The combinatoryadministration of FAK inhibitor (VS-6063) with anti-PD1 mAb synergistically increased anti-tumor response and survival outcome compared with single-agent therapy in the KL-mediatedsyngeneic orthotopic lung cancer model. By using GEMM-derived syngeneic cell lines, we haveevaluated the potential for creating innovative immunochemotherapies, customized for KL co-mutant lung adenocarcinomas with promising clinical potential. Furthermore, using this modelenables a deeper understanding of the KL mutant disease's pathogenesis, the impact of sex-biasedcancer development, and the assessment of novel immunochemotherapy treatment strategies in theKL genetic sub-type of lung adenocarcinoma.
Citation Format: Junghui Koo, Carol Tucker-Burden, Melissa Roy, Chunzi Huang, Wei Zhou, Melissa Gilbert-Ross, Haian Fu, Suresh S. Ramalingam, Adam I. Marcus. Unraveling synergistic therapeutic strategies involving FAK inhibition and immunotherapy using anti-PD1 antibody in KRAS and LKB1-driven lung 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 4047.
Abstract 4097: LNP-mRNA neoantigen vaccines to intercept progression of pre-invasive to invasive lung adenocarcinoma
Authors: He Yongfeng , Zhong Sijin Luo , Bhinder Bhavneet , Markowitz Geoffrey , Singh Arshdeep , Gardner Eric , Ko Myung Soo , Altorki Nasser K. , Jiang Shaoyi , Mittal Vivek 
Published: March 2024

Abstract
The widespread use of chest computed tomography in lung cancer screening has led to the detection of ground-glass opacity (GGO) nodules, which typically harbor pre-invasive or minimally invasive adenocarcinoma and 20-40% of GGO nodules progress to invasive lung adenocarcinoma within 4 years. Lack of approved treatments to intercept disease progression has imposed challenges in the clinical management of patients with GGOs. Previous studies showed that GGO nodules have substantially lower rates of HLA deletions than invasive/metastatic lung cancer, suggesting that GGO nodules constitute a critical window of vulnerability for immune interception. We therefore sought to identify the most immunogenic and cytotoxic neoantigens in patients with GGO nodules and to develop LNP-mRNA cancer vaccines to intercept the disease progression from pre-invasive to invasive adenocarcinoma. Whole exome and RNA sequencing of a large cohort (&gt;300) patients identified potential neoantigen candidates, with KRAS-G12C, KRAS-G12D and EGFR-L858R as the most frequently predicted shared neoantigens consistent with &gt;40% GGO patient population harboring either mutant KRAS or EGFR driver oncogenes. LNP-mRNA vaccines targeting KRAS-G12C and EGFR-L858R showed marked immunogenicity as determined by ELISPOT assays. Moreover, KRAS-G12C vaccination induced CD4+ T cell responses whereas EGFR-L858R vaccination triggered CD8+ T cell responses. Both these vaccines are being tested in GGO immunoprevention studies. Our data suggest the potential of KRAS and EGFR vaccines in the treatment of early disease, particularly in EGFR mutant patients who fail to respond to immunotherapy.
Citation Format: Yongfeng He, Sijin Luo Zhong, Bhavneet Bhinder, Geoffrey Markowitz, Arshdeep Singh, Eric Gardner, Myung Soo Ko, Nasser K. Altorki, Shaoyi Jiang, Vivek Mittal. LNP-mRNA neoantigen vaccines to intercept progression of pre-invasive to invasive lung adenocarcinoma [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 4097.
Abstract 4130: Targeting epigenetically-driven inflammation for PDAC metastasis prevention in high-risk individuals
Authors: Handler Jesse , Kalhor Reza 
Published: March 2024

Abstract
Background: Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer with a dire prognosis, in large part due to the late stage at which it is diagnosed in most patients. High-risk individuals (HRIs) identified through family history or germline genetic testing are candidates for imaging-based screening, yet even with intensive surveillance, metastasis often occurs between scans. Our study aims to address this critical clinical challenge by investigating the epigenetic determinants of PDAC metastasis and developing novel strategies for metastasis prevention in HRIs.
Methods: Innovative transplantation models of PDAC liver and peritoneal metastasis incorporating DNA barcodes for subclonal tracking were developed to facilitate the identification of subclones with high or low metastatic potential. An in-depth epigenomic characterization and comparison of these subclones was performed utilizing assay for transposase-accessible chromatin with sequencing (ATAC-seq) and RNA-seq.
Results: Metastasis-high subclones demonstrate widespread chromatin accessibility differences relative to their metastasis-low peers. These differences are linked to expression changes for genes involved in motility, differentiation, survival, and particularly inflammation. Top epigenetically activated genes in metastasis-high subclones include the pro-inflammatory cytokines IL-1α and IL-23α and the pro-inflammatory cytokine receptor IL-18R1.
Discussion: These findings highlight the role of epigenetic changes in PDAC metastasis, especially activation of inflammatory pathways resulting from altered chromatin accessibility. These insights provide a foundation for exploring anti-inflammatory agents for PDAC metastasis prevention. Targeting inflammation, alongside imaging-based screening, could significantly improve outcomes for HRIs.
Citation Format: Jesse Handler, Reza Kalhor. Targeting epigenetically-driven inflammation for PDAC metastasis prevention in high-risk individuals [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 4130.
Abstract 4133: Hyaluronidase inhibitor delphinidin inhibits cancer metastasis
Authors: McGuire Jeremy Jonathan , Taguchi Taketo , Tombline Greg , Paige Victoria , Janelsins Michelle , Gilmore Nikesha , Seluanov Andrei , Gorbunova Vera 
Published: March 2024

Abstract
Cancer remains a formidable global health challenge, with metastasis being a key contributor to its lethality. Abundant high molecular weight hyaluronic acid, a major non-protein component of extracellular matrix, protects naked mole rats from cancer and reduces cancer incidence in mice. Hyaluronidase plays a critical role in degrading hyaluronic acid and is frequently overexpressed in metastatic cancer. We investigated the potential of targeting hyaluronidases to reduce metastasis. High throughput screening identified delphinidin, a natural plant compound found in fruits and vegetables, as a potent hyaluronidase inhibitor. Delphinidin-mediated inhibition of hyaluronidase activity led to an increase in high molecular weight hyaluronic acid in cell culture and in mouse tissues, and significantly reduced proliferation, migration and invasion of breast (EO771), prostate (RM1), and melanoma (B16-F10) metastatic cell lines. Addition of exogenous hyaluronidase partially reversed all of these effects. Moreover, delphinidin treatment suppressed melanoma (B16-F10) metastasis in a spontaneous mouse model of metastasis. These results provide a proof of principle that inhibition of hyaluronidase activity suppresses cancer cell migration, invasion and metastasis. These results combined with the lack of adverse effect make delphinidin an attractive potential therapeutic option for inhibition of metastasis. We believe further investigation is warranted to fully elucidate the mechanisms and optimize the use of delphinidin in cancer therapy.
Citation Format: Jeremy Jonathan McGuire, Taketo Taguchi, Greg Tombline, Victoria Paige, Michelle Janelsins, Nikesha Gilmore, Andrei Seluanov, Vera Gorbunova. Hyaluronidase inhibitor delphinidin inhibits cancer metastasis [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 4133.