tbuckley/cabot-search huggingface dataset:
Abstract 1043: Identification of the novel immune synapse-localized proteome for immuno-oncology using Microscoop-induced targeted photo-biotinylation
Authors: Weng-Man Chong, Cecile Li, Chun-Kai Huang, Chantal Hoi Yin Cheung, Hsiao-Jen Chang, Chia-Wen Chung, Jung-Chi Liao
Journal: Cancer Research (2024)

Abstract Although tens of immune synapse (IS) protein species are known, there remain many unknown IS-localized protein species. Understanding the proteome of the IS between a target cell and a lymphocyte is crucial for advancing immuno-oncology. The low abundance of ISs and the lack of a definitive enrichment marker have limited efficient proteomic profiling. Here, we used Microscoop™, an innovative system that integrates microscopy, machine learning, and targeted photo-biotinylation to enable precise and spatially specific enrichment of IS proteins, thereby facilitating proteomic discovery of the IS. We utilized Raji B cells as antigen-presenting cells (APCs) and induced IS formation with Jurkat T cells. The system first employed immunofluorescence imaging of CD3, a common IS marker in Jurkat T cells, and used a convolutional neural network-based deep learning algorithm to train the recognition of ISs from CMTPX-stained Raji B cells. Our automated system then successfully achieved spatially-targeted biotin-tagging of proteins at ISs through thousands of fields of view of imaging, deep learning-driven pattern generation, and photochemical labeling. Subsequent streptavidin pull-down and mass spectrometry analysis enabled the identification of IS-specific proteins. Remarkably, our spatial proteomic approach led to the isolation and identification of hundreds of different species at the IS interface, including proteins associated with key components of T-cell receptor (TCR) signaling pathways such as the TCR/CD3 complex, Src and Tec family tyrosine kinases, and pivotal NF-kB signaling proteins. Beyond these, we also identified a significant enrichment of proteins not previously associated with the IS. Our study not only illuminates previously unknown aspects of immune regulation at the IS interface, but also shedded light on proteins potentially important for immuno-oncology. These insights have significant implications for cancer research, particularly in understanding and manipulating immune responses for therapeutic purposes. Citation Format: Weng-Man Chong, Cecile Li, Chun-Kai Huang, Chantal Hoi Yin Cheung, Hsiao-Jen Chang, Chia-Wen Chung, Jung-Chi Liao. Identification of the novel immune synapse-localized proteome for immuno-oncology using Microscoop-induced targeted photo-biotinylation [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 1043.
Abstract 4130: Targeting epigenetically-driven inflammation for PDAC metastasis prevention in high-risk individuals
Authors: Jesse Handler, Reza Kalhor
Journal: Cancer Research (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 1324: Superior anti-tumor activity of GL205, an allogeneic anti-CD5 CAR-NK for treating T-cell malignancies
Authors: Miyoung Jung, Seung Min Kim, Eunsol Lee, Hyunseung Sun, Jaeyoung Yoo, Hwi Wan Choi, Subin An, Sunglim Cho, Bokyung Min
Journal: Cancer Research (2024)

Abstract T cell malignancies are rare and intractable diseases with fewer treatment options and higher unmet needs compared to B-cell lymphomas. Chemotherapy such as CHOP has been used as the standard therapy for treatment of T cell malignancies, but clinical outcome is not a promising and alternative treatments are needed. Currently, Brentuximab Vedotin, an antibody-drug conjugate that targets CD30 is widely used for Hodgkin lymphoma, ALCL and CTCL. However, the application is limited to specific subtypes because CD30 expression is restricted to some subsets of T-cell lymphoma. CD5 is an attractive target for cancer immunotherapy because it is commonly expressed in most of T cell malignancies. Although CD5 CAR-T cell products have demonstrated the anti-cancer efficacy, there are several disadvantages including 1) challenges due to difficulties in manufacturing process caused by fratricide, 2) product contamination by CAR-introduced patient’s malignant T cells, 3) severe side effects such as CRS and neurotoxicity. Therefore, CD5 CAR-NK as allogeneic anti-tumor therapy can be an alternative for treatment of T cell malignancies. GL205, cord blood-derived CD5 CAR-NK, is genetically modified to express CD5-directed CAR and simultaneously produce IL-15 which supports the NK survival and proliferation. GL205 is ex-vivo expanded, cryopreserved cell therapy product comprising of pure NK cells (&amp;gt; 99%) with high CD5 CAR expression (&amp;gt; 90%). GL205 showed significantly higher in vitro direct-killing efficacy against CD5+ tumor cells compared to donor matched CBNK. IFN-γ and IL-15 release from GL205 was significantly increased after co-incubation with CD5+ tumor cells. In xenograft mouse model, GL205 administration exhibited a greater survival rate and low tumor burden compared to vehicle group. In addition, GL205 was detected in blood for 3 months, demonstrating in vivo long-term persistence. In conclusion, GL205 could be a valuable and off-the-shelf allogeneic therapeutic option for treating T cell malignancies. Citation Format: Miyoung Jung, Seung Min Kim, Eunsol Lee, Hyunseung Sun, Jaeyoung Yoo, Hwi Wan Choi, Subin An, Sunglim Cho, Bokyung Min. Superior anti-tumor activity of GL205, an allogeneic anti-CD5 CAR-NK for treating T-cell malignancies [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 1324.
Abstract 7041: Tumor-immune interactions and cisplatin resistance in localized muscle-invasive bladder cancer
Authors: Filipe La Fuente De Carvalho, Jihyun Lee, Kevin Bi, Breanna Titchen, Konrad Stawiski, Jihye Park, Amanda Garza, Daniel Michaud, Jennifer Guerriero, Elizabeth Mittendorf, Kent Mouw, Eliezer Van Allen
Journal: Cancer Research (2024)

Abstract Background: Cisplatin-based chemotherapy followed by radical cystectomy remains the standard-of-care treatment for patient with localized muscle-invasive bladder cancer (MIBC). Neoadjuvant clinical trials studying the combination of cisplatin-based chemotherapy and immune checkpoint blockade (ICB) in MIBC reported encouraging pathologic complete response rates. However, the molecular mechanisms and cellular programs involved in response and resistance to cisplatin and ICB in MIBC remain incompletely characterized. Our goal is to define cellular transcriptional programs and chromatin accessible regions in cancer cells and infiltrating immune cells associated with response and resistance to neoadjuvant systemic therapy. Methods: We performed single-cell Multiome ATAC and Gene expression sequencing (simultaneous identification of gene expression and open chromatin regions within the same cell) of tumors that had a complete response – “responders” – and tumors that had no response or progressed – “non-responders” – through neoadjuvant cisplatin-based chemotherapy (n=15). Single cell suspensions were prepared following the 10x Genomics protocol. Cell Ranger ARC was used for sequence alignment, peak calling, and generation of count matrices. Downstream single-cell gene expression analysis was performed with Scanpy and ATAC-seq with Seurat. Results: We identified two distinct urothelial cell populations in "responders" vs "non-responders" based on single cell gene expression and genome wide chromatin accessibility regions. Cancer cells in “non-responders” preferentially express basal cell gene expression signatures. “Non-responders” were significantly enriched in suppressive tumor-associated macrophages (TAMs). Interestingly, SPP1+ TAMs known to have a pro-tumoral role and promote resistance to ICB were exclusively identified in “non-responders”. Conclusion: Single cell and genome wide chromatin accessibility regions identify heterogenous urothelial cell populations expressing basal cell markers in tumors resistant to neoadjuvant cisplatin-based chemotherapy. “Non-responders” are significantly enriched with TAMs implicated in resistance to ICB. Future studies will better define the implications of these findings in cancer therapeutics for patients with MIBC. Citation Format: Filipe La Fuente De Carvalho, Jihyun Lee, Kevin Bi, Breanna Titchen, Konrad Stawiski, Jihye Park, Amanda Garza, Daniel Michaud, Jennifer Guerriero, Elizabeth Mittendorf, Kent Mouw, Eliezer Van Allen. Tumor-immune interactions and cisplatin resistance in localized 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 7041.
Abstract 7016: Plastic epigenome in youth: Insights from open chromatin in stem cells
Authors: Yu-Yu Liu, Chihiro Takeuchi, Satoshi Yamashita, Toshikazu Ushijima
Journal: Cancer Research (2024)

Abstract The presence of plasticity in the epigenomes of young individuals is suggested by the aggressive phenotypes observed in cancers among adolescent and young adults (AYAs), including gastric cancers. To demonstrate the presence of this plasticity and identify the underlying epigenomic characteristics in gastric stem cells during youth, we examined organoids established from murine stomach tissue and conducted single-cell RNA-seq and ATAC-seq using murine antrum-pyloric tissues at ages of 3 weeks and 50 weeks, corresponding to human infancy and middle-age adult, respectively. Organoids established from infant mice showed higher dependence to niche factors, and stronger response to cytokine signals. Ligand-receptor analysis using single-cell RNA-seq data of tissues showed that infant epithelial stem cells and stromal cells had stronger interactions. Both supported the plastic nature of infant gastric epithelial cells. Single-cell ATAC-seq enabled us to identify epithelial stem cell population in infant and middle-aged mice, and 71 and 118 chromatin peaks were specific to infant and adult stem cells, respectively. Motif enrichment analysis showed an enrichment of binding sites for bZIP family transcription factors in infants, and an enrichment of binding sites of a chromatin remodeling factor and a family of transcription factors in adults. Additionally, comparison between differentiated epithelial cells, marked by the pit cell marker Muc5ac, and stem cells, marked by Lgr5, showed more pronounced differences: 46,772 peaks specific to pit cells and 39,076 peaks specific to stem cells. Interestingly, regions specific to pit cells were enriched in binding sites of the chromatin remodeling factor and the family of transcription factors, identical to the open regions specific to adult stem cells. This suggested that the chromatin accessibility profile of aged stem cells approaches to that of differentiated cells, leading to a loss of stemness. The single-cell RNA-seq data also revealed an increase in interactions between differentiated epithelial cells and fibroblasts in aged mice, as opposed to infant, suggesting the emergence of aberrant interactions in aged stomach tissue. Collectively, our data suggested that chromatin accessibility of gastric stem cells undergo an epigenomic shift during aging, approaching to the profiles of differentiated cells and losing their plasticity, and that a specific chromatin remodeling factor and a family of transcription factors could be involved in the process. Citation Format: Yu-Yu Liu, Chihiro Takeuchi, Satoshi Yamashita, Toshikazu Ushijima. Plastic epigenome in youth: Insights from open chromatin in stem cells [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 7016.
Abstract 4585: Discovery of ETS-006, a highly potent YAP/TEADs PPI inhibitor with broad anti-tumor activity as a single agent
Authors: Jiajun Lu, Ming Gao, Wenpei Du, Xiaofei Fan, Jinping Li, Mengya Wang, Lijian Feng, Yingjie Li, Jiaqi Yao, Jiting Lu, Wenqi Cui, Qiangang Zheng, Jidong Zhu
Journal: Cancer Research (2024)

Abstract The transcription co-activators YAP, pairing with the TEAD family of transcription factors, serve as essential effectors of the conserved Hippo signaling pathway. Hippo kinase cascade controls YAP nuclear entry and binding with TEADs by modulating its phosphorylation and stability. Overexpression and activation of YAP/TAZ are frequently observed in a variety of cancers. It has been well established that YAP aberration contributes to cancer development, metastasis, immunosurveillance escape and drug resistance. Disruption of YAP/TEADs PPI is an effective approach to inhibit YAP transcriptional activity. We previously have reported the identification of YAP/TEADs PPI hit compound through the fragment-based screen and advanced the hit to lead compound ETS-003. Here we reported the preclinical candidate of YAP/TEADs PPI inhibitor ETS-006 with much more potent anti-tumor activity and favorable safety profile. Compared to TEAD palmitoylation inhibitor, ETS-006 could completely disrupt the interaction of YAP/TEADs, resulting in a more profound downregulation of YAP target gene expression. ETS-006 demonstrated more robust anti-tumor activity than the competitor’s YAP/TEADs PPI inhibitor in MPM CDX model with favorable ADME properties. Notably, ETS-006 showed promising efficacy across multiple solid tumor types, including head and neck squamous cell carcinoma, osteosarcoma, and triple-negative breast cancer with urgent unmet clinical needs. In conclusion, ETS-006 is a highly potent and orally available YAP/TEADs PPI inhibitor with broad anti-tumor activity as a single agent. Citation Format: Jiajun Lu, Ming Gao, Wenpei Du, Xiaofei Fan, Jinping Li, Mengya Wang, Lijian Feng, Yingjie Li, Jiaqi Yao, Jiting Lu, Wenqi Cui, Qiangang Zheng, Jidong Zhu. Discovery of ETS-006, a highly potent YAP/TEADs PPI inhibitor with broad anti-tumor activity as a single agent [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 4585.
Abstract 5351: Tumor PKC-Delta induces immune exclusion in non-small cell lung cancer
Authors: Xing Xing Fan
Journal: Cancer Research (2024)

Abstract The recruitment of a sufficient number of immune cells to induce an inflamed tumor microenvironment (TME) is a prerequisite for effective response to cancer immunotherapy. The immunological phenotypes in the TME of EGFR-mutated lung cancer were characterized as non-inflamed, for which immunotherapy is largely ineffective. To orchestrate host immunity against lung tumors, we proposed that PKCδ, a gatekeeper of immune homeostasis with kinase activity, is responsible for the un-inflamed phenotype in EGFR-mutated lung tumors. It promotes tumor progression by stimulating extracellular matrix (ECM) and PD-L1 expression which leads to immune exclusion and assists cancer cell escape from T cell surveillance. Ablation of PKCδ enhances the intratumoral penetration of T cells and suppresses the growth of tumors. Furthermore, blocking PKCδ significantly sensitizes the tumor to immune checkpoint blockade (ICB) therapy (αPD-1) in vitro and in vivo models. These findings revealed that PKCδ is a critical switch to induce inflamed tumors and consequently enhances the efficacy of ICB therapy in EGFR-mutated lung cancer. This opens a new avenue for applying immunotherapy against recalcitrant tumors. This work was funded by the FDCT project grant to Dr. Xing-Xing Fan (Grant no. 0058/2020/A2). Citation Format: Xing Xing Fan. Tumor PKC-Delta induces immune exclusion in non-small cell 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 5351.
Abstract 3770: Comparative analysis of single cell expression and digital spatial profiling in FFPE tumor tissues
Authors: Anthony Moore, Andrea O'Hara, Pranay Vishwanath, Laure Turner, Haythem Latif, Chris Mozdzierz, Ginger Zhou
Journal: Cancer Research (2024)

Abstract Formalin Fixed Paraffin Embedded (FFPE) tissues are a staple in clinical diagnostics associated with solid tumor. Next Generation Sequencing (NGS) approaches characterize genomes, epigenomes, transcriptomes, and proteomes from a single sample source. FFPE blocks from several different tumor tissue types were serially sliced into FFPE slides. Individual slides were then utilized to explore the genome, epigenome, single cell RNA-Seq (scRNA-Seq), and Digital Spatial Profiling (DSP). Here we present a comparative analysis of two transcriptomic modalities within one FFPE tissue sample: fixed-cell scRNA-Seq of the transcriptome and digital spatial profiling of the whole transcriptome. Independent analysis of scRNA-Seq and DSP identified common trends as well as distinct differences within the same sample. Comparative analysis within sample between modalities identified statistically significant differences, driven by local tumor microenvironment, but also highlighted commonalities between methods. Cross sample comparisons showed striking differences, as indicated by tumor type. These studies highlight the strengths of each assay individually, as well as the power of a dual-assay approach for comprehensive analysis of the tumor and its microenvironment. Conclusions from this standalone analysis were further aggregated into downstream multiomics analyses, including proteomics analysis, illustrating the expanding landscape of information that can be extracted from FFPE derived tissue and the potential for novel discovery and diagnostic power integrating these complex data types holds. Citation Format: Anthony Moore, Andrea O'Hara, Pranay Vishwanath, Laure Turner, Haythem Latif, Chris Mozdzierz, Ginger Zhou. Comparative analysis of single cell expression and digital spatial profiling in FFPE tumor tissues [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 3770.
Abstract 3783: Oral squamous carcinoma, LN metastasis
Authors: Hotaka Kawai, Htoo Shwe Eain, Toshiaki Ohara, May Wathone Oo, Yamin So, Hitoshi Nagatsuka
Journal: Cancer Research (2024)

Abstract Due to genetically unstable nature of cancer cells, they give rise to genetically different variant subclones inside a single tumor. To enable the development of more efficacious therapies, it is crucial to understand cancer heterogeneity and subclone characteristics. Oral squamous cell carcinoma (OSCC) has high heterogeneity and plasticity. C-X3-C motif ligand 1 (CX3CL1) is the chemokine with anti- and pro-tumor functions. Our study reported CX3CL1 functions on cancer subclones with different phenotypes, both in vivo and in vitro. We found that Mouse OSCC (MOC) 1 and MOC2 cells responded in similar manners to CX3CL1 in vitro. However, in vivo, CX3CL1 increases cellular differentiation in indolent cancer (MOC1) while increasing metastasis in aggressive cancer (MOC2). These phenomena are influenced by different phenotypic tumor microenvironments created by indolent and aggressive cancer. From there, we established that when aggressive cancer cells gain CX3CL1 expression, they stimulate protumor immune system, promoting cancer metastasis via lymphatic vessels. A similar phenomenon was observed in metastatic OSCC patient samples, where CX3CL1 expression became intense in metastasis regions, consistent with aggressive subclone (MOC2) character; we correctly predicted patient outcomes by using CX3CL1 as prognostic indicator for long-term follow-up in metastatic OSCC patients. In conclusion, CX3CL1 is the key factor for stimulating aggressive cancer subclones to create new lymphatic networks for lymph node metastasis. Citation Format: Hotaka Kawai, Htoo Shwe Eain, Toshiaki Ohara, May Wathone Oo, Yamin So, Hitoshi Nagatsuka. Oral squamous carcinoma, LN 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 3783.