tbuckley/cabot-search huggingface dataset:
Abstract 4873: Characteristics of TIM-3 in regulating T cell activity in the brain tumor microenvironment
Authors: None mingi song, Su Bin Won, Hyung-Seok Kim, Dae Yeon Kim, Ki Sun Kim, Su Jeong Gu, Chanju Lee, Hee Jung Yoon, Eun Jung Park
Journal: Cancer Research (2025)

Abstract T-cell immunoglobulin and mucin domain-containing molecule 3 (TIM-3), a member of TIM family, has been shown to exhibit diverse characteristics in a context-dependent manner. In this study, we investigated the characteristics of TIM-3 on T cells in the brain tumor microenvironment. First, using an intracranial syngeneic mouse model, we examined the expression of TIM-3 in the brain tumor microenvironment. Immunohistochemistry (IHC) revealed that TIM-3 as well as PD-1 was expressed on various cell types, including CD3-positive cells in brain sections of tumor-bearing mice. Similar expression patterns were observed in tumor-infiltrating lymphocytes (TILs) by using flow cytometry analysis. To investigate the role of TIM-3 in T cells within the brain tumor microenvironment, we utilized T-lymphocyte specific TIM-3 conditional knock-out (TIM-3fl/fl Lck-cre, TIM-3 cKO). TIM-3 cKO mice exhibit a higher CD8+/CD4+ TIL ratio in the ipsilateral brain regions compared to tumor-bearing wild-type (WT) mice after GL26 cell injection into the right hemisphere. Moreover, in-vivo experiments with TILs demonstrated the influence of TIM-3 on T cell functional activity within the brain tumor microenvironment. Collectively, these results suggest that TIM-3 of T cells have an influence on the immune microenvironment of brain tumors. Citation Format: mingi song, Su Bin Won, Hyung-Seok Kim, Dae Yeon Kim, Ki Sun Kim, Su Jeong Gu, Chanju Lee, Hee Jung Yoon, Eun Jung Park. Characteristics of TIM-3 in regulating T cell activity in the brain tumor microenvironment [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 4873.
Abstract 4879: Unveiling a key obstacle to effective antitumor immunity in T-cell-restricted tumors
Authors: David Kung-Chun Chiu, Xiangyue Zhang, Bowie Yik-Ling Cheng, Kazukuni Hayashi, Qiang Liu, Bo Yu, Ryan Lee, Catherine Zhang, Jayakumar Rajadas, Nathan E Reticker-Flynn, Erinn B Rankin, Edgar G Engleman
Journal: Cancer Research (2025)

Abstract Endogenous antitumor immune responses in cancer patients can lead to the formation of "inflamed" tumors, characterized by a significant infiltration of tumor-reactive T cells. However, the majority of patients fail to mount such robust immune responses, resulting in immune-evasive tumors. To explore the mechanisms underlying this failure, we established and compared spontaneous mouse models of hepatocellular carcinoma (HCC) with either an inflamed, T-cell-rich or non-inflamed, T-cell-deprived tumor microenvironment (TME). Intriguingly, non-inflamed tumor models exhibited splenomegaly and elevated plasma erythropoietin (EPO) levels despite the absence of anemia, and these effects were independent of tumor size. This finding raised the possibility that tumor-derived EPO might dictate tumor immunotype. Our investigations revealed that EPO ablation in non-inflamed HCC models led to a substantial increase in effector memory CD8 T-cell infiltration, reduced tumor burden, and even induced tumor regression. Conversely, enforced EPO expression in inflamed HCC models suppressed T-cell infiltration and promoted tumor progression. Further analysis of both human and mouse HCC tissues demonstrated that the erythropoietin receptor (EPOR) is predominantly expressed on tumor-associated macrophages (TAMs). Tumor-derived EPO interacts with EPOR on TAMs to autonomously establish a non-inflamed, immunosuppressive TME, effectively evading T-cell surveillance. Mechanistically, EPO-EPOR signaling reprograms TAMs toward an immunoregulatory phenotype via NRF2-mediated heme depletion. Disruption of this axis—through either tumor-derived EPO ablation or EPOR deletion on TAMs—transformed the TME into an inflamed, T-cell-rich TME, driving tumor regression regardless of tumor genotype. Notably, this immune reactivation synergized with immune checkpoint blockade therapy. In summary, the EPO/EPOR axis functions as a critical immunosuppressive switch, enabling tumors to escape immune surveillance. Its inactivation reprograms macrophages to foster antitumor immunity, offering a promising strategy to enhance the efficacy of immunotherapy in HCC and potentially other cancers. Citation Format: David Kung-Chun Chiu, Xiangyue Zhang, Bowie Yik-Ling Cheng, Kazukuni Hayashi, Qiang Liu, Bo Yu, Ryan Lee, Catherine Zhang, Jayakumar Rajadas, Nathan E Reticker-Flynn, Erinn B Rankin, Edgar G Engleman. Unveiling a key obstacle to effective antitumor immunity in T-cell-restricted tumors [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 4879.
Abstract 3018: Discovery of SIGX1094R, a novel FAK inhibitor simultaneously blocking FAK and SRC signaling
Authors: Haisheng Zhang, Shu Zhuo, Lei Zhang, Lin Li, Wanfen Peng, Fengtao Jiang, Yufang Chen, Lin Lin
Journal: Cancer Research (2025)

Abstract Diffuse gastric cancer (DGC) is a highly lethal malignancy with only minimally effective systemic therapies. Our previous studies identified the Focal Adhesion Kinase (FAK) as a novel and promising target for DGC. To enhance the efficacy of FAK inhibition in cancer therapy, we developed a potent small-molecule inhibitor, SIGX1094R. This inhibitor targets both FAK and the related kinase SRC, which complexes with FAK, whereas current FAK inhibitors in clinical trials only inhibit p-FAK.In DGC cell line models and mouse organoid models, SIGX1094R significantly inhibited cell growth and demonstrated much greater potency than current FAK inhibitors in clinical trials, with similar results observed in DGC patient-derived organoids. To further evaluate efficacy, we found that SIGX1094R significantly blocked tumor growth in several DGC patient-derived xenografts, whereas current first-line drugs demonstrated limited efficacy. This aligns with clinical results, highlighting SIGX1094R's strong potential to replace the existing standard of care. Additionally, SIGX1094R demonstrated significantly greater efficacy in ascites models (both in vitro and in vivo) compared to the current standard treatments. In addition to treating DGC, SIGX1094R shows promise in preclinical studies for treating ovarian, triple-negative breast, and pancreatic cancers. It also has high potential for use in combination therapies with targeted treatments for KRAS and EGFR mutations. GLP tox studies demonstrated that most of the lesions in high dose of SIGX1094R animals at the end of the recovery period were fully recovered.The drug received investigational New Drug (lND) clearance both from the U.S. Food and Drug Administration (FDA) and the National Medical Products Administration (NMPA) in China. SIGX1094R, poised to be the world’s first targeted therapy for DGC, is the inaugural project in a pipeline discovered by AI and validated using organoid disease models. Citation Format: Haisheng Zhang, Shu Zhuo, Lei Zhang, Lin Li, Wanfen Peng, Fengtao Jiang, Yufang Chen, Lin Lin. Discovery of SIGX1094R, a novel FAK inhibitor simultaneously blocking FAK and SRC signaling [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 3018.
Abstract 2385: Discovery of non-coding somatic driver mutations in single-cell chromatin accessibility data
Authors: Song Cao, Liting Zhang, Alla Karpova, Fernanda M. Rodrigues, Yingduo Song, Nadezhda V. Terekhanova, Benjamin J. Raphael, Ryan C. Fields, Feng Chen, Li Ding
Journal: Cancer Research (2025)

Abstract scATAC-seq data presents unprecedented opportunities to identify somatic mutations in regulatory regions. However, existing tools struggle to reliably detect somatic mutations from scATAC-seq data due to the unbalanced coverage between tumor and normal cells. To address this, we developed scVar, a pipeline designed to detect somatic mutations from scATAC-seq data. Applying scVar to snATAC-Seq data from about 200 tumor samples spanning 10 cancer types, we identified over 70, 000 somatic mutations, with 95% located in non-coding regions. Comparison with bulk WGS and WXS data demonstrated that scVar achieves high accuracy in detecting somatic mutations. Notably, scVar effectively recaptured the UV mutational signature in skin cancer. Variant allele frequency (VAF) analysis revealed an increase in VAF in snATAC-seq data compared to WXS data. For tumor suppressor genes such as TP53, VHL, BAP1, CDH1, CBFB, TGIF1, and ZNF750, homozygous mutations with VAFs approaching 1 were consistently detected in snATAC-seq data, emphasizing the critical role of biallelic variants in tumor initiation. We also observed recurrent TERT promoter mutations across 20 samples, with VAFs close to 1, which were associated with increased chromatin accessibility and expression in glioblastoma, but not in skin cancer. Additionally, novel promoter mutations, such as in CDK12, were linked to increased gene expression. These findings highlight the utility of scVar in uncovering somatic mutations and their functional effects in non-coding regions from scATAC-seq data. Citation Format: Song Cao, Liting Zhang, Alla Karpova, Fernanda M. Rodrigues, Yingduo Song, Nadezhda V. Terekhanova, Benjamin J. Raphael, Ryan C. Fields, Feng Chen, Li Ding. Discovery of non-coding somatic driver mutations in single-cell chromatin accessibility data [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 2385.
Abstract 3216: A dual-acting chimeric peptide inhibits tumor growth by inhibiting PD-L1 and inducing immunogenic cell death
Authors: So-Young Park, Smriti Gurung, Byungheon Lee
Journal: Cancer Research (2025)

Abstract Blockade of the immune checkpoint proteins such as PD-L1 enables to overcome the resistance of cancer cells against the immune surveillance. Nevertheless, the blockade therapy itself lacks cytotoxic killing ability to cancer cells. In this study, we exploited PD-L1-targeted cytotoxic peptides that block PD-L1 on the surface of tumor cells and induce the tumor cell death as well. As targeting peptides, we used PD-L1Pep-1 and PD-L1Pep-2 that bind to and block PD-L1. As a cytotoxic peptide, the KLAKLAKKLAKLAK peptide (named K) was fused to the targeting peptide. PD-L1Pep-1-K and PD-L1Pep-2-K decreased cell survival in PD-L1-expressing tumor cells. Both peptides were internalized into tumor cells through the receptor-mediated endocytosis and localized at lysosomes and also at mitochondria. The peptide-induced cell death was accompanied by an increase in the exposure of CRT on the cell surface and extracellular release of ATP and HMGB1, which are markers of immunogenic cell death (ICD). PD-L1Pep-2-K rekindled the T-cell activity including proliferation and cytokine secretion when co-cultured with tumor cells. Systemic administration of PD-L1Pep-2-K inhibited tumor growth more efficiently than PD-L1Pep2 and anti-PD-L1 antibody. These results suggest that the PD-L1-targeted cytotoxic peptide is a novel dual-acting therapeutic agent capable of PD-L1 blocking and ICD induction for cancer immunotherapy. Citation Format: So-Young Park, Smriti Gurung, Byungheon Lee. A dual-acting chimeric peptide inhibits tumor growth by inhibiting PD-L1 and inducing immunogenic cell death [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 3216.
Abstract 5797: Impact of baseline tumor size on response to anti-CD47 immunotherapy in an osteosarcoma mouse model
Authors: Raheleh Roudi, Iryna Vasylkiv, Laura Pisani, Tie Liang, Raya Saab, Heike Daldrup-Link
Journal: Cancer Research (2025)

Abstract Background and Purpose. Activation of tumor-associated macrophages (TAMs) by CD47 mAb therapy can be monitored with ferumoxytol-enhanced magnetic resonance imaging (MRI). The purpose of our study was to investigate if tumor size at baseline affects TAM response to CD47 mAb, as measured with ferumoxytol-MRI. Methods. Thirty female NOD scid gamma (NSG) mice with small-sized (tumor volume = 30 mm3), medium-sized (tumor volume = 500 mm3), and large (tumor volume = 1200 mm3) 143B osteosarcoma xenografts were treated with human CD47 mAb (10 mg/kg, day 1, 3, and 5 for 1 week) or PBS (control group). All mice underwent MRI scans at baseline and at one week after CD47 mAb or sham treatment. Post-treatment scans were obtained before and after intravenous infusion of ferumoxytol nanoparticles (30 Fe mg/kg). We measured tumor T2* relaxation times as a quantitive measure of nanoparticle retention in TAM. The tumor ferumoxytol enhancement, calculated as: ΔT2* = 100 * (T2*precontrast - T2*postcontrast) / T2*precontrast, was compared between experimental groups using exact two-sided Wilcoxon rank-sum tests. Histology served as standard of reference. Results. At baseline, tumors of CD47 mAb and PBS-treated mice demonstrated no significant difference in T2* relaxation time, regardless of tumor size (all p&amp;gt;0.05). After CD47 mAb therapy, tumors treated with CD47 mAb demonstrated significantly shorter T2* relaxation times compared to PBS-treated mice (all p&amp;lt;0.001). The tumor T2* enhancement was significantly higher in small tumors (ΔT2* = 41.3% +/- 2.182%) compared to large tumors (ΔT2* = 2.93% +/- 2.474%; p=0.001), indicating stronger nanoparticle phagocytosis in small sized tumors, apparently due to increased TAM activation. There was not statistically significance difference between T2* relaxation time of small and medium-sized tumors in all time points (all p&amp;gt; 0.05). Histopathological correlations confirmed a significantly higher number of CD80-positive TAMs in small sized tumors after CD47 mAb therapy (61.28% +/- 1.77%) compared to large sized tumors (3.38% +/- 0.81%, p&amp;lt;0.001). Conclusion. Tumor size at baseline affects TAM response to CD47 mAb. Smaller osteosarcomas exhibit a more pronounced TAM response to CD47 mAb therapy compared to larger tumors. Citation Format: Raheleh Roudi, Iryna Vasylkiv, Laura Pisani, Tie Liang, Raya Saab, Heike Daldrup-Link. Impact of baseline tumor size on response to anti-CD47 immunotherapy in an osteosarcoma mouse 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 5797.
Abstract 3864: AOH1996: A multi-faceted inhibitor of metastasis via PCNA and tumor microenvironment targeting
Authors: Robert G. Lingeman, Robert Hickey, Linda Malkas, Mustafa Raoof, Jacob Cawley
Journal: Cancer Research (2025)

Abstract Metastasis remains the leading cause of cancer-related mortality, emphasizing the urgent need for therapies to prevent and treat this process. AOH1996, a selective inhibitor of proliferating cell nuclear antigen (PCNA), has emerged as a promising agent with anti-metastatic properties. AOH1996 disrupts critical pathways such as angiogenesis, cancer cell migration, and tumor microenvironment modulation. Through bulk RNA-seq analysis of cancer cells, AOH1996 was found to downregulate genes involved in angiogenesis and migration, processes essential for metastasis. Functional assays using highly metastatic osteosarcoma cell lines revealed that AOH1996 inhibited cell proliferation and migration in both 2D monolayer and 3D spheroid models. In 3D cultures, which closely mimic the tumor microenvironment, AOH1996 significantly suppressed cell invasion and growth, demonstrating its efficacy in a more physiologically relevant context. The anti-metastatic potential of AOH1996 was further validated using an ex vivo Pulmonary Metastasis Assay (PuMA), where osteosarcoma cells implanted into mouse lungs were effectively killed by AOH1996. This highlights its ability to directly target metastatic cells in the lung. Complementary cell invasion assays using Matrigel showed that AOH1996 altered the morphology of invadopodia—structures critical for tissue invasion—rendering them non-functional and significantly reducing invasive capacity. Preliminary data from a Phase I clinical trial (NCT05227326) in patients with advanced, chemo-refractory solid tumors demonstrated AOH1996’s clinical potential. In one patient with pancreatic cancer, AOH1996 reduced the size of two liver metastases by 50%, underscoring its efficacy in a clinical setting. Tumor-associated macrophages (TAMs) facilitate immune evasion, angiogenesis, and metastasis. Oncogenic MYC influences the tumor microenvironment (TME) by recruiting TAMs to the TME. We have found that AOH1996 inhibits MYC expression in cancer cells, but not in non-malignant cells. We hypothesize that this suppression of MYC by AOH1996 disrupts the formation of a supportive metastatic niche through reduced TAM recruitment. Thus, AOH1996 may enhance immune responses and impede angiogenesis and metastasis. Together, these findings establish AOH1996 as a multi-faceted therapeutic with significant anti-metastatic potential. By targeting both PCNA-dependent processes and the tumor microenvironment, AOH1996 could provide a unique approach for combating metastatic cancers. Citation Format: Robert G. Lingeman, Robert Hickey, Linda Malkas, Mustafa Raoof, Jacob Cawley. AOH1996: A multi-faceted inhibitor of metastasis via PCNA and tumor microenvironment targeting [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 3864.
Abstract 5861: Characterizing an immune synapse between plasmacytoid dendritic cells and cancer cells that drives cancer cytotoxicity
Authors: Tobias Wang Bjerg, Ian Helstrup Nielsen, Sabina Sanchez Hernandez, Anders Laustsen, Isabella Barbutti, Shuli Svetitsky, James Lee, Rasmus Bak, Martin Jakobsen
Journal: Cancer Research (2025)

Abstract Background: Plasmacytoid dendritic cells (pDCs), a unique type of innate immune cells, are known to play an important role in fighting viral infections, especially due to their capacity to sense DNA/RNA nucleic acids by TLR7/-9, and production of type-I interferons. The role of pDCs in driving immunological effects in cancer development and mounting antitumoral responses remains to be elucidated, though few studies describe opposing outcomes in patients based on tumor infiltrating pDCs. These observations come with little evidence explaining the immunosuppressive or tumorigenic state of pDCs. Methods: To study fundamental anti-tumoral functions of pDCs we utilized a robust and validated in vitro stem-cell derived human pDC model. Importantly, this model permits genetic manipulation prior to pDC differentiation and enables large-scale co-culture studies with various cancer types. Using this model, we recently employed a CRISPR library screening approach to identify factors that aid the cytotoxic mechanisms of pDCs following co-culture with tumor cell lines. Results: Initially, using co-culture assays consisting of hematological, lung, or breast cancer cell lines in combination with in vitro generated pDCs, we demonstrated a time-dependent cytotoxic effect using Incucyte live imaging. Importantly, cytotoxic effects were elevated when pDCs had been stimulated with TLR9 agonists. We demonstrated that a direct cell-to-cell interaction was essential for pDC cytotoxicity, and that promoting stronger cell-to-cell interaction, by genetically modifying pDCs to express scFv targeting a tumor antigen, increased the killing effects. CRISPR knock-out of Granzyme B in pDCs did not remove the cytotoxic capabilities of pDCs. We are currently conducting a genetic screen to identify universal factors vital for pDC interactions and cytotoxicity effects in cancer settings. This preliminary data will be presented at the AACR meeting. Conclusion: Using in vitro-generated pDCs we explore an important anti-tumoral function of pDCs. If successful, our work can open for potential new therapeutics and prognostic possibilities in cancer treatment, harnessing the cytotoxic effects of pDCs. Citation Format: Tobias Wang Bjerg, Ian Helstrup Nielsen, Sabina Sanchez Hernandez, Anders Laustsen, Isabella Barbutti, Shuli Svetitsky, James Lee, Rasmus Bak, Martin Jakobsen. Characterizing an immune synapse between plasmacytoid dendritic cells and cancer cells that drives cancer cytotoxicity [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 5861.
Abstract 3844: Tumor endothelial cell lines and their use for the identification of new tumor vascular targets during dysbiosis
Authors: Samir V. Jenkins, Mohammad Alimohammadi, Kieng B. Vang, Robert J. Griffin, Ruud P. Dings
Journal: Cancer Research (2025)

Abstract The overall use of antibiotics has increased by more than 30% in recent years according to the centers of disease control and prevention (CDC). Moreover, many cancer patients are prescribed antibiotics, as a prophylactic or to treat infection, a frequent complication during cancer progression and treatment. Yet, tumor endothelial cell lines are scarce at best and tumor endothelial cell lines derived under dysbiotic pressure non-existent. In order to address this we generated ‘normal’ or orthobiotic and dysbiotic tumor endothelial cell lines. After validating their endothelial cell origin on a genomic, proteomic and functional level, we found that tumor endothelial cells derived from dysbiotic mice (TEC-Dys) were more sensitive to hypofractionated radiation doses (i.e. 6 Gy) as compared to tumor endothelial cells derived from orthobiotic mice, TEC-Ortho. In order to identify relevant tumor vasculature drug targets during dysbiosis, we used tandem mass tag mass spectroscopy and focused on the extracellular proteins significantly overexpressed in TEC-Dys, as compared to TEC-Ortho. C-Met fulfilled these criteria and we validated this histologically by comparing tumors with or without dysbiosis. Moreover, c-Met inhibitors Foretinib, Crizotinib, and Cabozantinib were significantly more effective against TEC-Dys than TEC-Ortho. Foretinib inhibited tumor growth to a greater extend during dysbiosis as compared to orthobiotic conditions. Thus, we surmise that tumor response in dysbiotic patients may be greatly improved by targeting dysbiosis-induced pathways, such as c-Met, as compared to the targets suppressed due to dysbiosis. These matched tumor endothelial cell lines generated under orthobiotic and dysbiotic conditions can now be used in in vitro and in vivo cell-based models, and provide an improved and specialized platform for current and next-generation anti-cancer drug discovery and development. Citation Format: Samir V. Jenkins, Mohammad Alimohammadi, Kieng B. Vang, Robert J. Griffin, Ruud P. Dings. Tumor endothelial cell lines and their use for the identification of new tumor vascular targets during dysbiosis [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 3844.