tbuckley/cabot-search huggingface dataset:
Abstract 5245: Anti-CSPG4 CAR-Macrophages synergize with anti-CD47 in melanoma cytotoxicity
Authors: Daniel Greiner, Qian Xue, Trinity Waddell, Minna Roh-Johnson
Journal: Cancer Research (2024)

Abstract While CAR T-cells have been a success in treating liquid tumors, these successes have not been replicated in solid tumors. There are several reasons for these challenges, including physical matrix barriers and increased tumor antigen heterogeneity in solid tumors. Macrophages are frequently found in melanoma tumors, even in those that have low T-cell infiltrate, suggesting macrophages are well equipped to penetrate the physical barriers surrounding solid tumors. Macrophages are also antigen-presenting cells, thus, if macrophages phagocytose the tumor, they will likely present additional antigens to T-cells, potentially enhancing the adaptive immune response in cancer treatment. Thus, we hypothesized that macrophages expressing chimeric antigen receptors (CAR-Macrophages or CAR-Ms) are able to access solid tumors, phagocytose cancer cells, and subsequently re-educate the tumor immune environment by directly polarizing tumor-associated macrophages and by presenting novel antigens to recruit and educate adaptive immune cells. To test these hypotheses, we generated CAR-Ms with primary human macrophages using an scFV specific to chondroitin sulfate proteoglycan 4 (CSPG4), a highly expressed antigen enriched and specific to melanoma tumors, and an intracellular activation domain to promote phagocytosis. We found that anti-CSPG4 CAR-Ms phagocytosed human melanoma cells at high efficiency, however, this phagocytosis did not result in high levels of melanoma cell cytotoxicity. To improve CAR-M-mediated melanoma cell death engulfment, we blocked the anti-CD47/SIRPα (“don’t eat me”) signaling axis with an anti-CD47 blocking antibody, which resulted in additive effects for phagocytosis, and a robust effect on the melanoma cell killing. Preliminary in vivo xenograft experiments suggest that anti-CSPG4 CAR-Ms alone delay melanoma growth. We are now testing whether combining anti-CD47 and CSPG4 CAR-Ms therapies in vivo can 1) further reduce primary tumor growth and 2) prevent recurrence following surgical resection by treating remnants of the tumor. Our work shows that CSPG4 CAR-M-mediated killing of CSPG4-positive cancer cells is significantly enhanced when in combination with anti-CD47 antibody treatment. Citation Format: Daniel Greiner, Qian Xue, Trinity Waddell, Minna Roh-Johnson. Anti-CSPG4 CAR-Macrophages synergize with anti-CD47 in melanoma cytotoxicity [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 5245.
Abstract 4410: The CpG island methylator phenotype is closely associated with prognosis in patients with oral squamous cell carcinomas
Authors: Masanobu Abe, Satoshi Yamashita, Toshikazu Ushijima, Kazuto Hoshi
Journal: Cancer Research (2024)

Abstract Few abnormalities are known to be closely associated with prognosis in OSCC cases. In this study, genomic abnormalities of cancer-related genes and epigenomic abnormalities of genes methylation-silenced in OSCCs were analyzed to identify abnormalities associated with prognosis. Thirty-nine OSCC cases and their surgical materials were analyzed for the presence of mutations using next-generation sequencing. Methylation status of promoter CpG islands of five genes was analyzed by methylation-specific PCR. Mutations in CRG, TP53 and PIK3CA were observed in 64.1%, 38.5%, and 33.3%, respectively, of the cases. However, no significant association between mutation status and overall survival (OS) was observed. Aberrant methylation of CMTM3, NKX2-3, RBP4, EGFLAM, and MAP6 were observed in 51.3%, 41.0%, 66.7%, 38.5%, and 41.0%, respectively. Methylation of NKX2-3, EGFLAM, and MAP6 were significantly associated with OS in OSCC cases (p=0.006, 0.006, and 0.012, respectively). Cases with methylation of CMTM3 and RBP4 showed a trend toward poor prognosis (p=0.052 and 0.059, respectively). Methylation profiles of the five genes indicated the presence of the CpG island methylator phenotype (CIMP), and the CIMP-positive cases showed poor prognosis (HR=20.5, p&amp;lt;0.001). In conclusion, CIMP was closely associated with the prognosis of OSCC cases. Citation Format: Masanobu Abe, Satoshi Yamashita, Toshikazu Ushijima, Kazuto Hoshi. The CpG island methylator phenotype is closely associated with prognosis in patients with oral squamous cell carcinomas [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 4410.
Abstract 1298: Assessing the impact of Medicaid expansion on colorectal cancer preventative services utilization
Authors: Paulette Omeaku
Journal: Cancer Research (2024)

Abstract Introduction: Colorectal cancer (CRC) is the second leading cause of cancer mortality. CRC screening rates have steadily risen and incidence rates around the nation have declined. To date, forty-one states have expanded Medicaid across the United States, with 9 states remaining that have not expanded. Although, access through insurance has increased, colorectal disparities in screening and mortality persist. Other studies have shown that screening guideline concordance can be inconsistent based on insurance type. Data suggests Medicaid enrollees are more likely to present advanced-stage cancers than those privately enrolled. The screening differences throughout the United States emphasize how complex colorectal cancer disparities are and how insurance may play a role. Aims: Our study aims to investigate the impact of Medicaid expansion on timely CRC screenings, specifically examining whether these effects differ by African Americans, Hispanics, and White Americans. Methods: Data was utilized from the Behavioral Risk Factor Surveillance System (BRFSS) to analyze timely CRC screening data of adults below 138% of the federal poverty level (FPL) of states with different Medicaid expansion statuses. Most recently available data was used in our analysis spanning the years 2014-2022 in all 50 states. States were stratified by dummy variables for Medicaid expansion and non-expansion status. Timely CRC screenings were determined by eligible respondent responses. Difference-in-difference analyses were used to study the effect of Medicaid expansion on timely CRC screenings in states with different Medicaid expansion statuses. Results: Our sample included 60.52% White Americans, 12.22% African Americans, and 16.41% Hispanics in both Medicaid expanded and non-expanded states. Sex and race had significant associations to Medicaid expansion status and timely CRC screenings, particularly when analyzing race for Hispanics and White Americans. Between 2014 and 2022, timely CRC screening for low-income adults in Medicaid expansion states was at 33.15% compared to 23.17% from non-expansion status states. Notably, adults aged 45-64 demonstrated the highest differences in timely CRC screenings for Medicaid-expanded states (12.26% and 18.98%) compared to non-expanded states (9.27% and 13.96%, respectively). Citation Format: Paulette Omeaku. Assessing the impact of Medicaid expansion on colorectal cancer preventative services utilization [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 1298.
Abstract 6752: Targeting of neoantigen cancer vaccines to antigen presenting cells results in faster and broader T cell responses whether encoded in DNA or mRNA
Authors: Brian T. Weinert, Lise Skullerud, Eirik Solbakken, Ana Textor, Mirjam Dürkoop, Inga Patrycja Winge, Gunnstein Norheim, Elisabeth Stubsrud, Stine Granum, Mikkel W. Pedersen, Håkan Norell
Journal: Cancer Research (2024)

Abstract Individualized cancer vaccines based on patient-specific neoantigens represent a groundbreaking approach in oncology, offering a highly individualized treatment option for cancer patients. Unlike traditional vaccines, which are designed to prevent diseases by stimulating an immune response against a specific pathogen, personalized cancer vaccines are therapeutic, aiming to treat cancer by training the immune system to recognize and attack the patient’s own cancer cells. The key is to induce a fast, strong, broad, and persistent CD8+ T cell response. Nykode Therapeutics has developed a platform that targets antigens directly to antigen presenting cells (APCs) using a modular dimeric protein format known as a VaccibodyTM. Individualized neoantigen vaccines delivered in a DNA-encoded Vaccibody format have been shown to induce strong and broad T cell responses in pre-clinical and clinical settings. Here, we wanted to determine if the APC-targeted approach leads to superior T cell responses if Vaccibody vaccines are encoded in mRNA and administered in a lipid nanoparticle (LNP) formulation. For this purpose, we designed and evaluated a model cancer vaccine composed of 20 unstructured 27 amino acid long neoantigens derived from the murine MC38 tumor model. A DNA-encoded Vaccibody vaccine elicited faster T cell responses compared to an untargeted mRNA-LNP-encoded vaccine. DNA-encoded Vaccibody responses were also broader, targeting a substantially greater number of neoantigens. Next, we compared the APC-targeting Vaccibody vaccine to an untargeted vaccine when both were formulated in an mRNA-LNP format. The APC-targeting Vaccibody vaccine elicited a greater breath and magnitude of T cell responses compared to the untargeted vaccine. Further studies to evaluate the functional differences associated with the various formats, in terms of T cell phenotype and response to tumor challenge, are ongoing. In summary, the data demonstrate that an APC-targeted Vaccibody vaccine containing MC38 neoantigens can be encoded in both DNA and mRNA-LNP to induce faster, broader, and stronger T cell responses compared to a non-targeted neoantigen vaccine. Citation Format: Brian T. Weinert, Lise Skullerud, Eirik Solbakken, Ana Textor, Mirjam Dürkoop, Inga Patrycja Winge, Gunnstein Norheim, Elisabeth Stubsrud, Stine Granum, Mikkel W. Pedersen, Håkan Norell. Targeting of neoantigen cancer vaccines to antigen presenting cells results in faster and broader T cell responses whether encoded in DNA or mRNA [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 6752.
Abstract 5783: Receptor tyrosine kinase Tyro3 interaction with ligands and inhibitors
Authors: Keisha Nicole Hardeman, Chrystal Starbird
Journal: Cancer Research (2024)

Abstract TAM receptors (Tyro3, Axl, Mer) are a sub-family of receptor tyrosine kinases that regulate cell survival and homeostasis primarily through their role in clearance of apoptotic cells. While several receptor tyrosine kinases (RTKs) are targeted in various types of cancer therapies, interest in Tyro3 as a potential target in breast cancers has only recently grown. Determining the structure of Tyro3 with and without tyrosine kinase inhibitors (TKIs) bound will provide important missing information to aid in the design of treatments that can be combined with existing cancer treatments, as dual treatment is often necessary. I have designed constructs that will be used for crystallization of the Tyro3 kinase domains. I mapped the full portion of the kinase (called "Small"), an extended kinase ("Big"), and a smaller catalytic domain ("Cat"). The kinases were made through a molecular cloning method (Gibson Assembly), sequence verified, and expressed in insect cells for large scale purification. Ni-NTA and gel filtration will be used, followed by crystallization and soaking with inhibitors. Citation Format: Keisha Nicole Hardeman, Chrystal Starbird. Receptor tyrosine kinase Tyro3 interaction with ligands and inhibitors [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 5783.
Abstract 7464: Tertiary lymphoid structures in pancreatic cancer: Biomarkers of immunogenic patients or direct contributors to anti-tumor immunity
Authors: Shrijan Khanal, Olivia Harder, Elijah Kirschstein, Morgan Mack, Carl Ware, Michael Gough, Kristina Young, Andrew J. Gunderson
Journal: Cancer Research (2024)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a cancer with low survival rates and currently no immunotherapy options. However, many tumors from PDAC patients can be heavily infiltrated with T and B cells associated with favorable survival outcomes indicating anti-tumor immunity is functional in certain patients. In some of these lymphocyte-inflamed PDAC tumors, spontaneous organization of tertiary lymphoid structures (TLS) is evident upon surgical resection and these patients have a clear survival advantage. TLS are predictive of immune checkpoint blockade response in some cancer types, yet PDAC patients, with or without TLS, are still insensitive to these strategies. To address this paradox, we evaluated surgically resected PDAC tumors from previously untreated patients and discovered that tumors with TLS (TLS+) recruited T and B cells with specific anti-tumor and memory phenotypes suggesting immunosurveillance of disease was enhanced. Furthermore, a subset of TLS+ patients contained germinal centers and improved humoral immune function corresponding to an increased neoantigen burden and long-term survival. When assessing gene expression differences between TLS+ and TLS- patients, operable inflammatory and immunosuppressive pathways emerged that could be therapeutically exploited to activate TLS neogenesis. To address these mechanistic questions, we have developed a method for inducing TLS formation in implantable mouse PDAC tumors in the orthotopic setting utilizing an antibody that agonizes the lymphotoxin beta receptor (LTBR) in mice bearing established PDAC tumors. These TLS are complexed with T cells, B cells, CXCL13+ cells, and PNAd+ HEV associated with reduced tumor growth, presence of lymphocyte-recruiting cancer associated fibroblasts and increases in anti-tumor T and B cell phenotypes. Interestingly, some mouse PDAC cell lines are resistant to TLS formation by LTBR agonism while others are susceptible offering a model to study patient heterogeneity. We will use this TLS+ PDAC mouse model to address how TLS may directly improve antigen-specific T cell and B cell immunity and elucidate the pathways that regulate TLS formation. These data will offer new strategies to overcome immunotherapy resistance in cancer patients. Citation Format: Shrijan Khanal, Olivia Harder, Elijah Kirschstein, Morgan Mack, Carl Ware, Michael Gough, Kristina Young, Andrew J. Gunderson. Tertiary lymphoid structures in pancreatic cancer: Biomarkers of immunogenic patients or direct contributors to anti-tumor 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 7464.
Abstract 6284: Multimoics reveal aberrant pathways and regulation of castration resistant and metastatic prostate cancer
Authors: Aaron M. Horning, Chia-Nung Hung, Brandon Liebermann, Chih-Wei Chou, Che-Kuang Lin, Yao Vickie Wang, Victor X. Jin, Michael A. Liss, Chiou-Miin Wang, Chun- Lin, Meizhen Chen, Tim H-M Huang, Chun-Liang Chen
Journal: Cancer Research (2024)

Abstract Prostate cancer is a highly heterogeneous disease and in the end, 30% of patients will experience metastatic and fatal castration resistant prostate cancer (mCRPC). In spite of the vigorous efforts to search the causes of metastatic CRPC (mCRPC), the mechanisms are still largely unresolved. To understand the progression of mCRPC, we utilized scRNA-seq to profile global expression patterns in LNCaP, LNCaP-Abl and PC3 representing castration sensitive and resistant states. ScRNA-seq revealed 335 and 2393 differentially expressed (DE) genes in early and advanced castration resistant states enriched in 43 and 163 aberrant pathways. These included focal adhesion, adherens junction, leukocyte transendothelial migration, ECM-receptor interaction, regulation of actins, gap junction, TGFb, WNT, Hippo, Ephrin and other pathways. Upregulation of these pathways predicted worst disease free/overall survival of The Cancer Genomes Atlas (TCGA) PC cohort using Kaplan-Meir estimation. Further scRNA-seq also indicated most of the pathways were also enriched in ex vivo circulating tumor cells derived from biochemical recurrent or mCRPC patients. Small molecule perturbation verified function of 9 pathways involved in cell proliferation, migration, invasion, and organoid formation of mCRPC cell lines and CTCs. We then delved into how these genes are regulated by the global chromatin landscape through Assay for Transposase-Accessible Chromatin and high throughput DNA-seq (ATAC-seq). In castration sensitive LNCaP, active chromatins are associated with genes but most of them are located in distal intergenic regions. Conversely, the majority (51.9-57.6%) of open chromatins in castration resistant PC cells are situated in promoters that lie within 1kb of transcription start sites. KEGG pathway enrichment analysis uncovered Hippo, Wnt, tight junction, adherens junction, circadian and other pathways that corroborate the scRNA-seq findings. GRO-seq data indicated that nascent transcription supports gene body transcription in castration resistant cells but leads to massive pausing in castration sensitive cells. Citation Format: Aaron M. Horning, Chia-Nung Hung, Brandon Liebermann, Chih-Wei Chou, Che-Kuang Lin, Yao Vickie Wang, Victor X. Jin, Michael A. Liss, Chiou-Miin Wang, Chun- Lin, Meizhen Chen, Tim H-M Huang, Chun-Liang Chen. Multimoics reveal aberrant pathways and regulation of castration resistant and metastatic prostate 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 6284.
A TBK1 variant causes autophagolysosomal and motoneuron pathology without neuroinflammation in mice
Authors: David Brenner, Kirsten Sieverding, Jahnavi Srinidhi, Susanne Zellner, Christopher Secker, Rüstem Yilmaz, Julia Dyckow, Shady Amr, Anna Ponomarenko, Esra Tunaboylu, Yasmin Douahem, Joana S. Schlag, Lucía Rodríguez Martínez, Georg Kislinger, Cornelia Niemann, Karsten Nalbach, Wolfgang P. Ruf, Jonathan Uhl, Johanna Hollenbeck, Lucas Schirmer, Alberto Catanese, Christian S. Lobsiger, Karin M. Danzer, Deniz Yilmazer-Hanke, Christian Münch, Philipp Koch, Axel Freischmidt, Martina Fetting, Christian Behrends, Rosanna Parlato, Jochen H. Weishaupt
Journal: The Journal of Experimental Medicine (2024)

Heterozygous mutations in the TBK1 gene can cause amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The majority of TBK1-ALS/FTD patients carry deleterious loss-of-expression mutations, and it is still unclear which TBK1 function leads to neurodegeneration. We investigated the impact of the pathogenic TBK1 missense variant p.E696K, which does not abolish protein expression, but leads to a selective loss of TBK1 binding to the autophagy adaptor protein and TBK1 substrate optineurin. Using organelle-specific proteomics, we found that in a knock-in mouse model and human iPSC-derived motor neurons, the p.E696K mutation causes presymptomatic onset of autophagolysosomal dysfunction in neurons precipitating the accumulation of damaged lysosomes. This is followed by a progressive, age-dependent motor neuron disease. Contrary to the phenotype of mice with full Tbk1 knock-out, RIPK/TNF-α-dependent hepatic, neuronal necroptosis, and overt autoinflammation were not detected. Our in vivo results indicate autophagolysosomal dysfunction as a trigger for neurodegeneration and a promising therapeutic target in TBK1-ALS/FTD.
Abstract 6180: Tumor microenvironment phenotypes predict recurrence in African Americans diagnosed with colorectal cancer: A comparative study of manual grading with digital pathology
Authors: Dongling Wu, Rong Xia, Mouyed Alawad, Lili Lee, Tamas Gonda, Wenqing Cao, Sean Hacking
Journal: Cancer Research (2024)

Abstract African Americans face a higher rate of colorectal cancer (CRC) incidence and mortality compared to other ethnicities. Identifying key prognostic factors is essential for better outcomes in this group. This study focused on the prognostic value of stromal grading in the tumor microenvironment (TME) of African American CRC patients, using both manual grading and digital pathology. A retrospective analysis of CRC cases in African Americans was conducted. Two cohorts were established: a control cohort (patients without recurrence) and a recurrence cohort (patients with recurrence). Stromal grading was performed manually, categorizing tumors into Grade 1 (low risk), Grade 2 (moderate risk), and Grade 3 (high risk), and we also quantified the TME percentages by digital pathology: myxoid, collagen, immune and tumor. In the control cohort (N=40), stromal grading identified 30 Grade 1, 7 Grade 2, and 3 Grade 3 cases. Conversely, the recurrence cohort (N=17) demonstrated a starkly different distribution, with 1 Grade 1, 3 Grade 2, and 13 Grade 3 cases. The Chi-square statistic was notably significant (p&amp;lt;0.0001), indicating a strong association between higher stromal grades and the likelihood of recurrence. By unpaired t-test, high myxoid stroma (p&amp;lt;0.0001), low collagen (p&amp;lt;0.0001), and low tumor (p=0.0002) by digital pathology were associated with recurrence. TME phenotypes are a significant prognostic and recurrence indicator in African American patients with CRC. The marked difference in stromal grades and digital pathology features between the control and recurrence cohorts suggests that higher stromal grades, along with higher myxoid, lower collagen and lower tumor percentages are associated with an increased risk of recurrence. These findings underscore the need for tailored therapeutic strategies and more vigilant surveillance in African American patients exhibiting high-risk TME phenotypes. The efficacy of manual and digital pathology evaluation of the TME also warrants further exploration to enhance prognostic accuracy and treatment personalization. Citation Format: Dongling Wu, Rong Xia, Mouyed Alawad, Lili Lee, Tamas Gonda, Wenqing Cao, Sean Hacking. Tumor microenvironment phenotypes predict recurrence in African Americans diagnosed with colorectal cancer: A comparative study of manual grading with digital pathology [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 6180.