tbuckley/cabot-search huggingface dataset:
Abstract 3978: B-cell activating factor (BAFF) enhances antitumor immunity
Authors: Khaled Aziz, Kabeer Munjal, Kathryn Howe, Mark Yarchoan
Journal: Cancer Research (2024)

Abstract Immunotherapies that modulate T cell function have been firmly established in cancer immunotherapy, whereas the potential for B cells in the antitumor immune response is not as well understood. B cell-activating factor (BAFF) is a cytokine belonging to the TNF ligand family that activates B cells and is linked to autoimmunity. Our preliminary research has identified BAFF as a target for enhancing antitumor immunity through enhancing presentation of tumor neoantigens and inducing tertiary lymphoid structures which can orchestrate tumor-specific T cell immune responses and correlate with improved clinical response. Since broad activation of B cell response could be detrimental and possibly induce autoimmune side effects, identification of specific B cell receptors that coordinate anti-tumor immunity is prudent. BAFF has three known receptors (BAFF-R, TACI and BCMA), and the effects of these specific BAFF ligand-receptor interactions on antitumor immunity are not known. Here we first generated BAFF-overexpressing cell lines using genomic editing [KPC-BAFF (pancreas), B16F10-BAFF (melanoma), and PancO2-BAFF (pancreas)] and examined their tumor growth in syngeneic immunocompetent host. Secondly, we investigated the effects of BAFF-overexpression on tumor response when individual receptors are knocked out using BAFF-R-KO, TACI-KO and BCMA-KO mice. Our results show significantly hindered tumor growth when the BAFF expressing stable cell lines are introduced to immunocompetent host, compared to parental cell lines. Tumor response experiments in receptor knockout mice is currently in progress. Successful identification of the BAFF receptor candidate that drives anti-tumor response is an exciting prospect for clinical translation. Development of agonists for the specific receptor may allow selective modulation of this particular B cell function in context of cancer therapy without perturbation of broad systemic humoral immunity. Citation Format: Khaled Aziz, Kabeer Munjal, Kathryn Howe, Mark Yarchoan. B-cell activating factor (BAFF) enhances 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 3978.
Abstract 1859: Diverse CD28-binding IgG and heavy chain-only antibodies for T-cell engager development
Authors: Katherine Lam, Shirley Zhi, Lucas Kraft, Elena Vigano, None Wei, Cristina Faralla, Esther Odekunle, Kelly Bullock, Erin Marshall, Melissa Cid, Grace Leung, Lindsay DeVorkin, Sherie Duncan
Journal: Cancer Research (2024)

Abstract Engagement of the CD28 co-receptor by T-cell engager (TCE) molecules can enhance activation, proliferation, and anti-tumor activities, particularly in immunosuppressive tumor microenvironments. In this study, we present data on a diverse panel of CD28-binding IgG and heavy chain-only (HCAb) antibodies for T-cell co-stimulation. Our diverse panel of CD28-binding antibodies add co-stimulatory building blocks to our TCE repertoire. Using single B cell-screening, we identified fully human IgG and HCAb binders to human and non-human primate CD28 with a high degree of sequence diversity. We selected a subset of antibodies for expression and assessed binding to both human and cynomolgus CD28-expressing cells. These antibodies displayed a wide range of binding avidities in the sub-nanomolar to micromolar range, and epitope binning analysis identified seven epitope communities. Co-stimulatory activity for a subset of molecules was assessed in vitro. Antibodies displayed a wide range of crosslinked T-cell activation with the majority showing no activation independent of crosslinking. Data presented here describe a diverse set of CD28-binding antibodies ready for engineering into co-stimulatory TCEs. Combining these molecules with our TCE platform or other T-cell activating strategies will enable development of novel TCE modalities with co-stimulatory function for diverse tumor targets. Citation Format: Katherine Lam, Shirley Zhi, Lucas Kraft, Elena Vigano, Wei, Cristina Faralla, Esther Odekunle, Kelly Bullock, Erin Marshall, Melissa Cid, Grace Leung, Lindsay DeVorkin, Sherie Duncan. Diverse CD28-binding IgG and heavy chain-only antibodies for T-cell engager development [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 1859.
Abstract 3584: Context matters: Genomic profiling of PR isoform-specific actions in breast cancer stem cells reveals novel therapeutic insights for ER+ breast cancer
Authors: Noelle E. Gillis, Thu H. Truong, Jessica Finlay-Schultz, Carol A. Sartorius, Carol A. Lange
Journal: Cancer Research (2024)

Abstract Exposure to progesterone is a recognized risk factor for breast cancer, and PGR polymorphisms are associated with various malignancies. The two progesterone receptor (PR) isoforms, full length PR-B and truncated PR-A, are expressed from the PGR gene in breast tissue and play crucial roles in normal physiology. An imbalance in the expression ratio of these isoforms, favoring increased levels of PR-A, is common in breast cancer and is associated with resistance to tamoxifen in Luminal A-type tumors. Notably, PRs have recently been implicated in promoting endocrine resistance and driving the expansion of cancer stem-like cell (CSC) populations implicated in early dissemination and maintenance of metastatic populations. Because prior gene expression studies were primarily conducted in 2D culture conditions, the isoform-specific molecular and epigenetic mechanisms underlying PR actions in advanced ER+ breast cancer remain elusive. Our goal was to define progesterone-driven gene expression in CSC cells by employing transcriptomic profiling of T47D cells cultivated in spheroid-culture conditions (3D) expressing exclusively PR-A or PR-B. Utilizing CUT&amp;RUN, we have mapped the genomic binding sites unique to each PR isoform and identified shared sites. This genomic data has been integrated with phenotypic studies in cells expressing a single PR isoform. Our findings indicate that PR-A acts as a regulator of the cell cycle and senescence, while PR-B plays a pivotal role in cell metabolism and intracellular signaling. We find little overlap between PR-regulated gene sets derived from the same hormone-treated cells harvested from 2D relative to 3D conditions. Our genomic profiling of PRs in this 3D model system has unveiled novel strategies to combat CSC outgrowth and late recurrence in luminal breast cancer patients. This work has shifted our prior understanding of the role of PRs in gene regulation within the CSC population, and offers potential insights for therapeutic interventions in ER+ breast cancer. Citation Format: Noelle E. Gillis, Thu H. Truong, Jessica Finlay-Schultz, Carol A. Sartorius, Carol A. Lange. Context matters: Genomic profiling of PR isoform-specific actions in breast cancer stem cells reveals novel therapeutic insights for ER+ breast 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 3584.
Abstract 3982: Evaluating the effects of obesity on immune responses in renal tumors
Authors: Francesca Dempsey, Lyse Norian
Journal: Cancer Research (2024)

Abstract Understanding the effects of obesity on cancer progression and treatment is a critically important area of research. Obesity is reaching epidemic proportions in our country and is known to increase the risk for many cancers, including renal cell carcinoma, which is among the ten most common cancers in both men and women. Our lab has shown that obesity leads to worse outcomes in advanced renal cancer patients treated with immunotherapy as compared to lean patients, but the cause for this difference is unknown. To investigate this further, we utilized a murine model with diet-induced obese mice and lean mice that were challenged with orthotopic renal tumors. The tumors grew out over three weeks and were harvested for flow cytometry staining. We stained for markers associated with immune function to better characterize what might be causing patients with obesity to be less responsive to immunotherapy. Our preliminary findings show that DIO mice had a greater tumor burden than lean controls over time. We also found that there compositional differences in multiple subsets of T cells in DIO versus lean mice. In the future, we will expand our murine studies to evaluate the phenotype and function of both tumor cells and immune cells. Additionally, we will continue these studies in human samples to further examine associations between obesity and immunotherapy outcomes. Citation Format: Francesca Dempsey, Lyse Norian. Evaluating the effects of obesity on immune responses in renal tumors [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 3982.
Abstract 1707: YAP-driven epigenetic reprogramming in head and neck cancer
Authors: Adam Officer, Farhoud Faraji, Sydney Ramirez, Alon Goren, Pablo Tamayo, J. Silvio Gutkind
Journal: Cancer Research (2024)

Abstract The ability to measure tumor evolution is difficult due to a lack of model systems able to capture tumor initiation, development, and invasion. We have developed a Dox-inducible spatiotemporally controlled HPV- and YAP-driven model of head and neck squamous cell carcinoma (HNSCC) with a well-defined cancer stem cell population. In order to better understand the epigenetic reprogramming associated with tumorigenesis we have systematically characterized the chromatin accessibility, histone landscape and YAP binding sites in this model. Cell lines were generated from tongue epithelia of normal and Dox-induced tumor-containing mice. Gene expression was measured using RNA-seq and chromatin accessibility was measured using ATAC-seq. CUT&amp;Tag for H3K27me3, H3K27ac, and YAP was used to measure epigenetic reprogramming and YAP-DNA interactions. Differential gene expression shows that genes involved in hormone signaling, glutathione-related metabolism, fatty acid metabolism and p53 signaling were highly enriched in the normal tongue suggesting a change in metabolism upon tumorigenesis.Differential ATAC-seq peaks with higher binding levels in the normal tongue showed enrichment for p53 motifs as well as homebox motifs including Otx2, GSC and CRX suggesting p53 signaling is lost upon carcinogenesis and lineage determination is altered. Motifs for TEAD, AP-1, and KLF5 were enriched in the tumor-specific ATAC-seq peaks showing that YAP is involved in chromatin accessibility changes. CUT&amp;Tag for YAP shows clear YAP binding near canonical YAP target genes including Axl, Ccn1, Ccn2 and Birc3. YAP peaks with higher binding in the normal tongue cell line were enriched for RUNX2 and p63 motifs and peaks higher in the tumor contained KLF5 motifs showing YAP is directly involved in the reprogramming of lineage determination. Multi-omics integration shows YAP-driven chromatin remodeling is associated with differential expression of genes involved in keratin production, EGFR and ER signaling. Direct epigenetic characterization of YAP involvement in tumor initiation is key to understanding the mechanisms of tumorigenesis in head and neck cancer. This work shows that YAP directly binds and affects the expression of genes involved in lineage determination and growth factor signaling to induce cancer progression and generate a cancer stem cell population. Citation Format: Adam Officer, Farhoud Faraji, Sydney Ramirez, Alon Goren, Pablo Tamayo, J. Silvio Gutkind. YAP-driven epigenetic reprogramming in head and neck 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 1707.
Abstract 2849: Palbociclib as a novel therapeutic for desmoplastic small round cell tumor
Authors: Justin W. Magrath, Shruthi Sanjitha Sampath, Dane A. Flinchum, Alifiani B. Hartono, Ilon N. Goldberg, Julia R. Boehling, Suzana D. Savkovic, Sean B. Lee
Journal: Cancer Research (2024)

Abstract Desmoplastic small round cell tumor (DSRCT) is an aggressive, pediatric cancer caused by the EWSR1-WT1 fusion oncoprotein. Targeted therapies are lacking and the current standard of care, multimodal therapy, is insufficient, leading to a 5-year survival rate of less than 25%. While the EWSR1-WT1 oncoprotein is critical to growth in vitro, its importance has yet to be examined in vivo. Further, the set of EWSR1-WT1 downstream targets critical to oncogenesis and the mechanism by which the two EWSR1-WT1 isoforms regulate them remain underinvestigated. Here we generate a toolkit of DSRCT cell lines that deplete EWSR1-WT1 in a doxycycline (dox)-inducible manner. This toolkit enabled us to establish the essentiality of EWSR1-WT1 not only in vitro but also for the first time in vivo. Using this toolkit, we performed RNA sequencing on four DSRCT cell lines and established the most comprehensive analysis of EWSR1-WT1 downstream targets to date. We discovered novel mechanistic insights into EWSR1-WT1 functionality including the uniqueness of its transcriptional alterations as compared to native WT1, the direct role of EWSR1-WT1 binding in gene upregulation, and the dominant role of the E-KTS isoform in transcription. Given the rarity of DSRCT, we focused on downstream targets with existing inhibitors and perform a drug screen that identified the CDK4/6 inhibitor palbociclib as a novel DSRCT therapeutic. We found that the E-KTS isoform of EWSR1-WT1 binds to the CCND1 promoter, leads to CCND1 expression, and stimulates DSRCT growth through the CCND-CDK4/6-RB axis. Palbociclib treatment conversely reduced DSRCT growth by preventing retinoblastoma phosphorylation and blocking the transition from G1 to S phase. Palbociclib treatment was effective not only in vitro but also in vivo where it significantly reduced tumor growth in two xenograft models of DSRCT. Given these novel findings and palbociclib’s previous approval by the FDA for the treatment of breast cancer, we advance palbociclib as an exciting DSRCT therapy that warrants urgent clinical investigation. Citation Format: Justin W. Magrath, Shruthi Sanjitha Sampath, Dane A. Flinchum, Alifiani B. Hartono, Ilon N. Goldberg, Julia R. Boehling, Suzana D. Savkovic, Sean B. Lee. Palbociclib as a novel therapeutic for desmoplastic small round cell tumor [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 2849.
Abstract 1857: Development of monoclonal antibodies against CD44v specifically expressed in cancers
Authors: Yukinari Kato, Hiroyuki Suzuki, Mika K. Kaneko
Journal: Cancer Research (2024)

Abstract CD44 is a transmembrane glycoprotein that binds to the extracellular matrix including hyaluronic acid. Human CD44 has 19 exons, 10 of which are commonly present in all isoforms. CD44 standard isoform (CD44s) is composed of the common exons, and is expressed in many cell types. CD44 variants (CD44v) are produced by alternative splicing, in which the remaining nine variant exons are inserted into the CD44 standard isoform in various combinations. The CD44 isoforms have overlapping and unique functions. Both CD44s and CD44v harbor hyaluronan-binding motifs that promote interaction with the tumor microenvironment, which activate various signaling pathways in tumor cells. CD44v is mainly expressed in epithelial cells and is involved in cell adhesion, proliferation, and survival. Overexpression of CD44v is observed in many solid tumors and plays an important role in invasion, metastasis, and acquisition of stemness. In this study, we employed the Cell-Based Immunization and Screening method (CBIS method), and established highly sensitive anti-CD44 monoclonal antibodies (mAbs) using CD44v3-10-overexpressed cell lines as immunogens. After that, we determined the epitopes by enzyme-linked immunosorbent assay and investigated their applications. As a result, we successfully established eight mAbs against each CD44v (v3 to v10), which can be used for flow cytometry, western blotting, and immunohistochemistry. Furthermore, some of them exhibited cancer specificity against pancreatic cancers, colorectal cancers, gastric cancers, or oral cancers, indicating that established anti-CD44v mAbs are useful for the antibody therapies. Citation Format: Yukinari Kato, Hiroyuki Suzuki, Mika K. Kaneko. Development of monoclonal antibodies against CD44v specifically expressed in cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1857.
Abstract 2129: Efficacy and underlying mechanisms of surufatinib combined with PD-1 monoclonal antibody and chemotherapy in pancreatic cancer
Authors: Nan Zhang, Ru Jia, Guanghai Dai
Journal: Cancer Research (2024)

Abstract Background: A phase 1b/2 study (NCT05218889) of surufatinib combined with camrelizumab, nab-paclitaxel, and S-1 (NASCA) as first-line therapy for metastatic pancreatic adenocarcinoma has shown promising results, potentially overcoming the limitations of current pancreatic immunotherapies. Animal studies are underway to further explore the synergistic effects and mechanisms of this combined therapeutic approach. Methods: Genetically engineered KPC mouse cells were used to establish a subcutaneous transplantation tumor model in female mice, which were then divided into control group, AG group (nab-paclitaxel + gemcitabine), and NASCA group. Tumor metrics were recorded until euthanasia after 21 days. Blood and tumor samples were analyzed using Flow Cytometry. Results: Compared with the control group, the NASCA and AG groups demonstrated tumor volume reductions of 14.7% (p=0.172) and -0.4% (p=0.972) on day 7, respectively. At day 14, the reductions were 48.8% and 29.9% (p&amp;lt;0.001*, p=0.002*). At day 21, the reductions were 37.4% and 21.5% (p=0.001*, p=0.144). The tumor growth inhibitions (TGIs) for NASCA and AG group were 56.7% (p&amp;lt;0.001*) and 21.2% (p=0.36), respectively. Compare to AG group, the tumor volume reduction in NASCA group were 15.1% (p=0.050*), 26.9% (p=0.001*) and 20.3% (p=0.116), respectively. And the TGIs for NASCA group compare AG group was 45.0% (p=0.020*). Distinguishingly, the NASCA group, when compared to the AG group, had a heightened proportion of M1 macrophages (28.5% vs. 15.5%, p=0.019*), mCD68+ Macrophages (99.7% vs. 99.1%, p=0,014*) and mPD-1+/mCD8+ T cells (24.8% vs. 9.8%, p=0.03*). Furthermore, T-regulatory cells (T-regs) in peripheral blood demonstrated uniformity across the groups, were no statistically. RNA-seq analysis revealed that the NASCA significantly suppressed multiple anti-angiogenic pathways while enhancing the cytokine pathway (p=0.005*), indicating potential immune system activation. Conclusion: The NASCA group outperformed the AG group in controlling tumor growth and early tumor shrinkage, potentially due to macrophage polarization regulation. Further research is vital to understand the benefits of integrating targeted therapy, immunotherapy, and chemotherapy for pancreatic cancer. Citation Format: Nan Zhang, Ru Jia, Guanghai Dai. Efficacy and underlying mechanisms of surufatinib combined with PD-1 monoclonal antibody and chemotherapy in pancreatic 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 2129.
Abstract 3550: PerturbDB: A resource for revealing gene functions and cancer-associated phenotypes
Authors: Bing Yang, Man Zhang, Yanmei Shi, Yi-Ming Dong, Xingyu Ma, Jingyuan Zhang, Daning Lu, Jian-You Liao, Dong Yin
Journal: Cancer Research (2024)

Abstract Perturb-seq is a high-throughput technique that combines clustered regularly interspaced short palindromic repeats (CRISPR)-based screens with single-cell RNA sequencing (scRNA-seq) readouts for high-content phenotypic screens to comprehensively map the transcriptional effects of genetic perturbations, showing great advantages in revealing disease-associated gene functions and mechanisms in high volumes. Despite the rapid accumulation of Perturb-seq datasets, no dedicated database exists for reusing these valuable information. In this study, we developed a platform called PerturbDB (http://research.gzsys.org.cn/perturbdb) to facilitate users to unveil genotype-phenotype relations, especially gene functions and regulatory networks involved in several classical cancer associated phenotypes using 37 Perturb-seq datasets from 15 studies. By reanalyzing 3,429,829 single-cell transcriptomes from the knockdown of 3214 genes across 10 different cell lines, we identified 749 classical cancer phenotype-related genes and 373 functional gene clusters annotating potential novel functions. Utilizing Marker genes scoring and the InferCNV algorithm, we identified genes involved in 9 malignant phenotypes, which consists of sustaining proliferative signaling (362 genes), resisting cell death (120 genes), inducing angiogenesis (145 genes), tissue invasion and metastasis (321 genes), enabling replicative immortality (160 genes), deregulating cellular metabolism (247 genes), avoiding immune destruction (95 genes), unlocking phenotypic plasticity (231 genes), and chromosome instability (231 genes). Additionally, functional clusters were calculated utilizing Principal Component Analysis (PCAs) and the HDBSCAN package to introduce unknown gene functions related to the cancer associated phenotypes. Perturbation clusters (PCs) were identified by comparing similarities in the transcriptomes of perturbed cells, suggesting individual genes in the same functional cluster perform similar gene functions, and therefore novel functions of 735 genes can be inferred from the known functions of neighboring genes. The PGSEA tool was developed to facilitate functional analysis of genes not yet included, which helps users to predict gene functions through a combination of PerturbDB datasets and personalized RNA-seq datasets. This study will greatly expand our understanding of genes involved in emblematic cancer associated phenotypes and their coordinated functions and regulatory networks. Citation Format: Bing Yang, Man Zhang, Yanmei Shi, Yi-Ming Dong, Xingyu Ma, Jingyuan Zhang, Daning Lu, Jian-You Liao, Dong Yin. PerturbDB: A resource for revealing gene functions and cancer-associated phenotypes [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 3550.