tbuckley/cabot-search huggingface dataset:
Abstract 2628: Generation of multi-antigen specific T cells for ovarian cancer using Prussian Blue nanoparticles and photothermal therapy
Authors: Erin E. Grundy, Abigail Lee, Samantha Chin, Melissa Hadley, Danielle Schmidt, Loretta Wang, Olivia Cox, Khadra Omar, Catherine M. Bollard, Rohan Fernandes, Katherine B. Chiappinelli
Journal: Cancer Research (2024)

Abstract The immunosuppressive nature of ovarian cancer (OC) allows these tumors to evade the immune system, contributing to late-stage diagnoses and poor clinical outcomes for patients. However, a higher number of tumor-infiltrating lymphocytes is associated with improved clinical outcomes in OC. One type of lymphocyte, the T cell, can traffic to the tumor and kill tumor cells. We have shown that treating tumor cells with Prussian Blue nanoparticles and photothermal therapy (PBNP-PTT) results in immunogenic cell death, a form of cell death that is visible to the immune system, including T cells. PBNP-PTT-treated tumor cells were then used to expand tumor-specific T cells from partially genetically matched healthy donors against breast and brain cancer cell lines. These expanded T cells were better able to recognize and kill the target tumor cell lines than bulk unexpanded T cells from the same donors. Hence, we hypothesized that using PBNP-PTT-treated OC cells would allow us to expand a polyclonal tumor-specific T cell product that is cytolytic against OC cells in vitro and in vivo.We first evaluated whether multi-antigen OC-specific T cells could be expanded from partially genetically matched healthy donors and confirmed that PBNP-PTT elicited immunogenic cell death in the HLA-A*02:01 human OC cell lines Hey and TykNu. Using our established in vitro T cell expansion protocol, we then successfully expanded T cells from multiple HLA-A*02:01 healthy donors (n=3) against these cell lines. Functional analyses—including interferon-gamma ELISPOT, multi-color flow cytometry, and cytotoxicity assays—demonstrated that the expanded T cells had enhanced anti-tumor responses against OC cell lines compared to bulk unexpanded T cells derived from the same donors. Current work is expanding this approach to a syngeneic murine setting in C57BL/6J mice. Moreover, we will evaluate HLA-matched T cells and tumor cells from patients with OC ex vivo. Collectively, these efforts serve as a novel approach towards a curative immunotherapy for OC. Citation Format: Erin E. Grundy, Abigail Lee, Samantha Chin, Melissa Hadley, Danielle Schmidt, Loretta Wang, Olivia Cox, Khadra Omar, Catherine M. Bollard, Rohan Fernandes, Katherine B. Chiappinelli. Generation of multi-antigen specific T cells for ovarian cancer using Prussian Blue nanoparticles and photothermal 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 2628.
Abstract 2638: Sensitizing immunotherapy-refractory prostate cancer to immune checkpoint blockade therapy with optimized ketogenic diet regimens
Authors: Sean Murphy, Sharif Rahmy, Dailin Gan, Jun Li, Xuemin Lu, Xin Lu
Journal: Cancer Research (2024)

Abstract The purpose of this study is to investigate strategies for enhancing immune checkpoint blockade (ICB) therapy in prostate cancer (PCa). To achieve this, we established a series of ICB-resistant PCa cell lines derived from a previously sensitive cell line, which originated from a murine model of metastatic PCa. Notably, we observed a reduction in major histocompatibility complex (MHC) class I protein levels in the resistant sublines. Our study demonstrated synergistic efficacy through the combination of anti-PD1 and anti-CTLA4 antibodies with histone deacetylase inhibitor (HDACi) vorinostat, a cyclic ketogenic diet (CKD), or β-hydroxybutyrate (BHB) supplementation. Importantly, these interventions significantly delayed PCa tumor progression. Furthermore, our analysis revealed that the effects of these interventions were contingent on both BHB and adaptive immunity. In-depth single-cell transcriptomic and proteomic profiling unveiled mechanisms involving cancer-cell-intrinsic changes (upregulated MHC class I molecules) and extrinsic factors, including CD8+ T cell chemoattraction, M1/M2 macrophage rebalancing, monocyte differentiation toward antigen-presenting cells, and reduced neutrophil presence. In conclusion, our findings provide valuable insights into the potential clinical utility of combining HDACi and optimized ketogenic diet regimens to enhance ICB therapy for PCa. Citation Format: Sean Murphy, Sharif Rahmy, Dailin Gan, Jun Li, Xuemin Lu, Xin Lu. Sensitizing immunotherapy-refractory prostate cancer to immune checkpoint blockade therapy with optimized ketogenic diet regimens [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 2638.
Abstract 3669: Clinical application of urinary DNA methylation biomarkers for identifying patients with non-muscle invasive bladder cancer
Authors: Giancarlo Bonora, Ziqi Zhu, Billie Gould, Binggang Xiang, Kemin Zhou, Shidong Jia, Roger Li, Pan Du
Journal: Cancer Research (2024)

Abstract Introduction Differences in DNA methylation along cell-free DNA (cfDNA) fragments are known to exist between cancer patients and healthy individuals. Profiling these aberrant methylation patterns in urinary cfDNA (ucfNDA) holds great promise for the non-invasive detection and monitoring of bladder tumors, including non-muscle invasive bladder cancer (NMIBC). Here, we analyzed fragment-level DNA methylation patterns in urine samples obtained prior to repeat transurethral resection of a bladder tumor (reTURBT) from a cohort of NMIBC patients. The results were compared to traditional clinical disease assessment and mutation-based tumor fractions. We found a strong concordance between DNA methylation abnormality and clinical diagnosis, as well as tumor fractions, highlighting the potential of epigenetic alterations as a non-invasive indicator of bladder cancer status. Methods Patients with high-risk NMIBC (n = 30) were prospectively enrolled prior to reTURBT. The PredicineEPIC™ genome-wide methylation analysis and PredicineBEACON™ MRD profiling was performed on pre-repeat TURBT urine samples. Abnormally methylated genomic fragments were detected against a background model built from a panel of plasma samples from healthy donors. Results DNA methylation abnormality was significantly higher (p = 4.8 × 10−6) in samples classified as NIMBC positive by a clinical pathologist (n = 19) compared to negative samples (n = 11), as well as compared to hold-out healthy donor samples (n=24; p = 7.0 × 10−9). Classifying the samples based on a DNA methylation score cut-off derived from healthy donor samples, 24/30 samples showed concordant disease status. Furthermore, DNA methylation abnormality scores correlated positively with mutation-based tumor fractions (r = 0.62), with higher grade samples showing a stronger correlation (r = 0.81; n = 13) than lower grade samples (r = 0.54; n = 17). Conclusion We demonstrate the utility of methylation patterns extracted ucfDNA samples obtained prior to reTURBT to detect and monitor NMIBC. Urinary DNA methylation patterns were highly concordant with clinical pathology status and as well as tumor fractions determined from mutation analysis. Citation Format: Giancarlo Bonora, Ziqi Zhu, Billie Gould, Binggang Xiang, Kemin Zhou, Shidong Jia, Roger Li, Pan Du. Clinical application of urinary DNA methylation biomarkers for identifying patients with non-muscle invasive bladder 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 3669.
Abstract 4299: A lineage-specific role of oncogenic protein kinase Cι in lung adenocarcinoma
Authors: Duy T. Nguyen, Ning Yin, Capella R. Weems, Lee Jamieson, Kayleah Meneses, Yi Liu, Nicole R. Murray, Alan P. Fields
Journal: Cancer Research (2024)

Abstract Lung adenocarcinoma (LUAD), the most prevalent subtype of lung cancer, can arise from two different cell populations: alveolar type 2 (AT2) cells and bronchiolar club cells. By utilizing genomic data from the cancer genome atlas program, human LUAD cell lines, and the well-characterized LSL-KrasG12D/Trp53-/- (KP) mouse model, we demonstrated that tumors arising from club cells are much more aggressive and follow a different trajectory of tumorigenesis when compared to those arising from AT2 cells. Intriguingly, our data strongly suggest that expression and signaling activity of protein kinase C iota (PKCι) can profoundly affect the cell of origin and oncogenic signaling pathways employed by resultant tumors. Specifically, KP-mediated transformation of club cells appears to be dependent on PKCι-ELF3-NOTCH3 and PKCι-YAP1 signaling axes, while AT2 cell malignancy is dependent on the PKCι-independent WNT signaling. In addition, club-cell-origin tumors exhibit an enrichment of cancer stem cells and increased infiltration of immunosuppressive myeloid cells in comparison to AT2-cell-origin tumors. This results in accelerated progression and increased likelihood of metastasis by LUAD tumors that originate from club cells. Taken together, our results indicate that PKCι expression and signaling activity can profoundly influence the cells of origin, tumor trajectories, and therapeutic vulnerabilities of LUAD tumors. Citation Format: Duy T. Nguyen, Ning Yin, Capella R. Weems, Lee Jamieson, Kayleah Meneses, Yi Liu, Nicole R. Murray, Alan P. Fields. A lineage-specific role of oncogenic protein kinase Cι in 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 4299.
Abstract 4272: Disruption of hyaluronan metabolism alters glioma cell proliferation by ligand dependent and independent mechanisms
Authors: Edward R. Neves, Joseph Mueller, Achal Anand, Kimberly Selting, Hui Xu, Roddel Remy, Brendan Harley, Sara Pedron-Haba
Journal: Cancer Research (2024)

Abstract Hyaluronan (HA) is the main constituent of the brain extracellular matrix and is an essential component of the glioblastoma (GBM) tumor microenvironment. The biosynthesis and catabolism of hyaluronan has multiple roles in tissue architecture and cell signaling. Dysregulation of these mechanisms is crucial in pathological processes such as cancer, inflammation or tissue remodeling. The role of HA is believed to be strongly dependent on its size (molecular weight), location, and cell receptor density and activity. HA is produced intracellularly by HA synthases (HAS1-3) and can also be catabolized endogenously by hyaluronidases (HYAL1-3).The fabrication of controlled microenvironments provided by three dimensional (3D) models helps to elucidate the role of HA signaling in GBM tumors. We exploit here the advantages of these models to understand the role of hyaluronan in the local behavior of GBM after radiation therapy and selected targeted inhibitors. We have established engineered brain tumor biomaterials based on functionalized hydrogels to monitor the response of patient-derived xenograft cell populations with different molecular signatures in combination with microfluidic devices. We have analyzed shifts in metabolism, hyaluronan secretion, as well as hyaluronan synthetic enzymes (HAS) and hyaluronidases (HYAL) activity in an array of patient derived GBM cells. We reveal that endogenous HA plays a role in mitochondrial respiration and cell proliferation in a tumor subtype dependent manner. We also show that HA fragments can enhance tumor metabolism and growth through ligand dependent and independent mechanisms. We provide bioengineered platforms and strategies to predict and stratify tumors in order to achieve more efficient combinatorial treatments targeting endogenous hyaluronan production. This work emphasizes the potential of these preclinical models to predict and accelerate cancer treatments, more relevant in malignancies with limited treatment options. Citation Format: Edward R. Neves, Joseph Mueller, Achal Anand, Kimberly Selting, Hui Xu, Roddel Remy, Brendan Harley, Sara Pedron-Haba. Disruption of hyaluronan metabolism alters glioma cell proliferation by ligand dependent and independent mechanisms [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 4272.
Abstract 4270: Differential expression of the αVβ3 integrin affects small extracellular vesicle cargo and promotes small extracellular vesicle pro-tumorigenic activity <i>in vivo</i> via its downstream effector, NgR2
Authors: Cecilia E. Verrillo, Fabio Quaglia, Nicole Naranjo, Anna Testa, Lucia R. Languino
Journal: Cancer Research (2024)

Abstract It is known that small extracellular vesicles (sEVs) are released from cancer cells and contribute to cancer progression via crosstalk with recipient cells. These sEVs are being investigated as powerful biomarkers and possible therapeutic agents for prostate cancer (PrCa), which remains the leading cause of cancer death among men in the United States. We have previously reported that sEVs expressing the αVβ3 integrin, a protein upregulated in aggressive neuroendocrine prostate cancer (NEPrCa), contribute to neuroendocrine differentiation (NED) in recipient cells. sEVs used in this study were isolated by iodixanol density gradient and characterized by nanoparticle tracking analysis, immunoblotting, and single vesicle analysis. Our proteomic profile of sEVs containing αVβ3, when compared to control sEVs, shows a downregulation of typical effectors involved in apoptosis and necrosis, and an upregulation of tumor cell survival factors. This subset also contains an αVβ3 downstream effector, NgR2, a member of the Nogo receptor family and a novel marker for NEPrCa. We have previously shown that NgR2 promotes NED and cell motility, and upregulates RhoA, a protein associated with aggressive phenotypes of PrCa. In this study, we show that the expression of NgR2 increases tumor growth in vivo. We also show that the downregulation of NgR2 inhibits tumor growth and NED. Furthermore, we report that sEVs containing αVβ3 are loaded with higher amounts of NgR2 as compared to sEVs that do not express αVβ3. Mechanistically, we demonstrate that sEVs containing NgR2 do not affect the sEV marker profile, but, when injected in vivo intratumorally, they promote tumor growth and induce NED. We confirm that the transfer of NgR2 into recipient cells is sufficient to promote tumor growth and show that NgR2 mimics the effect of sEVs containing αVβ3 since it displays increased growth of NgR2 transfectants in vivo, as compared to control cells. Overall, our results describe a new mechanism mediated by sEVs containing αVβ3 and NgR2 that promotes cancer progression. Acknowledgements: NIH R01-CA224769; DoD W81XWH2210826 Citation Format: Cecilia E. Verrillo, Fabio Quaglia, Nicole Naranjo, Anna Testa, Lucia R. Languino. Differential expression of the αVβ3 integrin affects small extracellular vesicle cargo and promotes small extracellular vesicle pro-tumorigenic activity in vivo via its downstream effector, NgR2 [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 4270.
Abstract 2989: MicroRNA profiling in human samples and cell lines uncovers eight key players in the cisplain resistance of HGSOC
Authors: Mariela Rivera-Serrano, Marienid Flores, Jose Rolon, Victor Reyes, Fatma Valiyeva, Pablo E. Vivas-Mejia
Journal: Cancer Research (2024)

Abstract Metastasis and drug resistance remain significant contributors to cancer-related mortality globally. In ovarian cancer, a substantial 70% of cases develop resistance to the front-line therapy, cisplatin. Despite numerous proposed mechanisms for cisplatin resistance, the complete molecular events leading to this phenomenon in ovarian cancer remain incompletely understood. Mounting evidence suggests that dysregulation of microRNAs (miRNAs) plays a pivotal role in carcinogenesis, including the development of drug resistance. While various miRNAs have been identified in ovarian cancer samples and cell lines, few studies have compared miRNA expression in human paraffin ovarian samples and cisplatin-resistant high-grade serous ovarian cancer (HGSOC), the most prevalent and malignant of gynecological malignancies. This study aimed to identify key miRNAs implicated in cisplatin resistance. We performed miRNA expression profiles in RNA isolated from human paraffin ovarian tumors and ovarian cancers cell lines. Eight miRNAs were commonly increased in paraffin samples and cisplatin resistant ovarian cancer cells. Targeting these miRNAs with inhibitors significantly reduced cell proliferation by more than 50% for miR-203a, miR-96-5p, miR-10a-5p, miR-141-3p, miR-200c-3p, and miR-182-5p, and to a lesser extent, miR-296-5p and miR-1206. Inhibitors demonstrated a reduction in cell migration for all targets except miR-200c-3p and miR-10a-5p. Analysis of online databases, literature reports, and molecular pathway construction revealed that these eight miRNAs regulate key molecular pathways associated with cell proliferation, primarily through PTEN regulation in cisplatin-resistant HGSOC cells. Interrogation of the KM plotter patient database revealed that high expression of miR-1206, miR-10a, miR-141, and miR-96 correlates with a poor prognosis in ovarian cancer patients. These findings position these eight miRNAs as potential therapeutic targets and markers for cisplatin response in ovarian cancer therapy. Citation Format: Mariela Rivera-Serrano, Marienid Flores, Jose Rolon, Victor Reyes, Fatma Valiyeva, Pablo E. Vivas-Mejia. MicroRNA profiling in human samples and cell lines uncovers eight key players in the cisplain resistance of HGSOC [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 2989.
Abstract 2629: N6AMT1-mediated DNA 6mA modification in DNA repetitive elements LINE-1 dynamically regulates the IFN signal pathway in colorectal cancer
Authors: Ze Yuan, Xiaoxia Liu, Xiaolin Wang, Yanxin Luo, Huichuan Yu
Journal: Cancer Research (2024)

Abstract Background: DNA N6-methyldeoxyadenosine (6mA) modification is the most prevalent DNA modification in prokaryotes, like bacteria, which participates in the host defense system. However, the presence and function of DNA 6mA in eukaryotes remains elusive. Many studies have reported that DNA 6mA modification is distributed across the genome and regulates transcription and the activity of transposable elements, in which the DNA 6mA methyltransferases and demethylases are involved, including the methyltransferase N6AMT1. LINE-1 is a genome-wide DNA repetitive element that acts as a diagnostic and prognostic biomarker for colorectal cancer. Therefore, we aimed to map the DNA 6mA in LINE-1 and investigate its role in the colorectal cancer (CRC) development. Methods: The restriction-enzyme-digestion assay followed by quantitative PCR (6mA-RE-qPCR) was used to evaluate the LINE-1 DNA 6mA levels in the tumor and normal tissues. The DNA Nanopore sequencing was utilized to determine DNA 6mA and 5mC modifications. After the knockdown of N6AMT1, the dynamic changes of LINE-1 DNA 6mA methylation and RNA transcription under various stresses were determined by 6mA-RE-qPCR and qPCR, and the subsequent RNA-seq was performed to explore the downstream regulated pathways. Results: The DNA 6mA methylation in LINE-1 is highly variant in the tumor and normal tissues, and it was significantly less prevalent in tumor tissues. The genomic distribution of LINE-1 DNA 6mA is significantly different from that of LINE-1 5mC. The LINE-1 DNA 6mA methylation and RNA transcription levels were dynamically changed in response to various stimuli, including 5-FU and H2O2. Knockdown of N6AMT1 downregulated LINE-1 DNA 6mA methylation and RNA transcription, promoted the proliferation, migration and invasion of CRC cells in vitro, and suppressed the IFN-gamma pathway. The co-culture assay showed N6AMT1 facilitated chemotaxis of macrophages and cytotoxicity of T cells via the IFN-gamma signal pathway. Conclusions: The heterogeneity of DNA 6mA methylation in LINE-1 and its dynamic change in response to stimuli indicate a biological role of LINE-1 6mA methylation in the primary and adaptive tumor heterogeneities, which provides a novel insight into cancer development. The N6AMT1-mediated DNA 6mA modification in LINE-1 regulates CRC development through the IFN-gamma pathway. Keywords: N6AMT1, LINE-1, DNA 6mA methylation, colorectal cancer Citation Format: Ze Yuan, Xiaoxia Liu, Xiaolin Wang, Yanxin Luo, Huichuan Yu. N6AMT1-mediated DNA 6mA modification in DNA repetitive elements LINE-1 dynamically regulates the IFN signal pathway in colorectal 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 2629.
Abstract 2972: Senescent macrophages drive tumorigenesis by limiting antitumor immunity
Authors: Luis I. Prieto
Journal: Cancer Research (2024)

Abstract A big challenge in oncology is tumor heterogeneity, as the same type of tumor can manifest differently across patients. Our current cancer therapies focus on targeting malignant cells without considering how the tumor microenvironment influence tumorigenesis or changes in response to treatment. Therefore, identifying effective therapies that restrict tumor growth and progression while restoring optimal tissue and organ function is imperative. Here, we propose a potential strategy to delay the frequency of lung tumorigenesis and reduce progression by selectively targeting tumor-promoting senescent cells that arise with advancing age, prolonging antitumor immunity. Using lung tumor-prone mice, we found that senescent cells, specifically senescent alveolar macrophages, accumulate early in hyperplastic lesions. Mechanistically, these macrophages upregulate the cell cycle regulator p16Ink4a; express the cell surface protein CXCR1; they are distinct from other established subsets; are sensitive to senolytic interventions; have a tumor-promoting secretome, including SPP1; and express immunosuppressive factors that modulate the antitumor immune response. Selective clearance of senescent macrophages attenuates adenoma development, indicating they, at least in part, promote tumorigenesis. Importantly, we observed alveolar macrophages with these properties accumulating in treatment-naive human early-stage lung adenocarcinoma in situ, indicating that the cellular senescence program in macrophages is a conserved etiology. We also found that senescent alveolar macrophages accumulate in otherwise naturally aged normal mouse lungs and their persistence correlates with increased inflammation. Collectively, our findings suggest that targeting senescent macrophages may constitute a potential therapeutic intervention to postpone or attenuate lung cancer during the early stages of the disease. Citation Format: Luis I. Prieto. Senescent macrophages drive tumorigenesis by limiting antitumor immunity [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 2972.