tbuckley/cabot-search huggingface dataset:
Abstract 118: Development of a novel murine model, NCG-M/hIL15, for enhanced post-HSC transplantation immunoreconstruction
Authors: Huiyi Wang, Jun Xing, Jialu Fan, Yuan Fan, Jing Zhao, Xiang Gao, Cunxiang Ju
Journal: Cancer Research (2024)

Abstract Advances in the field of immunology and hematopoietic stem cell (HSC) transplantation have prompted the development of murine models that faithfully recapitulate human immune responses. We present the NCG-M/hIL15 model, an innovative advancement in the realm of preclinical research, addressing two key challenges associated with existing models: the limited capacity for human natural killer (NK) cell regeneration in NCG-M and the suboptimal reconstitution of T cells, myeloid lineage cells in NCG-hIL15 mice. Compared to the conventional NCG-M model, the NCG-M/hIL15 model demonstrates a significant improvement in its ability to regenerate human NK cells post-HSC transplantation. This advancement offers a valuable tool for studying NK cell biology, immune surveillance, and antitumor responses. Furthermore, when compared to the NCG-hIL15 model, the NCG-M/hIL15 model outperforms in the reconstitution of human T cells and myeloid lineage cells, contributing to a more comprehensive simulation of human immune responses. The overall survival of mice in this model is notably stable, further enhancing its utility for long-term immunological studies. The NCG-M/hIL15 model not only advances our understanding of human immune responses but also has significant implications for the development of novel immunotherapies and the preclinical evaluation of HSC transplantation strategies. This novel murine model offers a more accurate representation of the human immune system, with the potential to expedite the development of innovative therapeutic interventions. We present this model as a valuable addition to the preclinical research toolkit, promising a deeper understanding of immunology and a brighter future for clinical applications. Citation Format: Huiyi Wang, Jun Xing, Jialu Fan, Yuan Fan, Jing Zhao, Xiang Gao, Cunxiang Ju. Development of a novel murine model, NCG-M/hIL15, for enhanced post-HSC transplantation immunoreconstruction [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 118.
Abstract 6839: Comprehensive transcriptomic analysis of acquired resistance after immune-checkpoint inhibitors in non-small cell lung cancer
Authors: Cheol Yong Joe, Yeong Hak Bang, Sehhoon Park, Hyun Ae Jung, Jong-Mu Sun, Yoon-La Choi, Jin Seok Ahn, Myung-Ju Ahn, Se-Hoon Lee
Journal: Cancer Research (2024)

Abstract Background: Treatment of lung cancer has changed dramatically with the use of immune checkpoint inhibitors (ICI). Nevertheless, most patients underwent drug resistance even though they initially showed a response to ICI, and there is an unmet need to delineate the mechanism. Method: We analyzed RNA sequencing data of paired pre- and post-ICI samples from 31 NSCLC patients. Among them, we identified 17 patients who underwent acquired resistance (AR) who initially showed partial or complete response or stable disease lasting more than six months, and the remaining 14 patients who showed primary resistance (PR) to ICI. The analysis was performed using a tumor microenvironment (TME) classifier, classifying immune-enriched [IE], immune-enriched and fibrotic [IE/F], fibrotic [F] and immune-desert [D] subtype, and CIBERSORTx, the immune cell deconvolutional analysis tool. Results: Most patients with AR were initially classified as IE or IE/F subtypes (N=12, 70.6%), but six out of 14 with PR (42.8%) showed IE or IE/F subtypes. Among 12 patients with initial IE or IE/F subtypes, seven (58.3%) patients turned into the D subtype after AR to ICI. Most patients initially classified as D or F subtypes (N=5, 29.4%) maintained their subtypes (N=4, 80%) after AR.When assessing the pre-ICI samples, memory B cell was enriched, and M2 macrophage and regulatory T cell were depleted in AR patients compared to PR. The memory B cell and resting memory CD4+T cell decreased, and M2 macrophage increased after AR to ICI. These immune cell composition changes were not observed in PR patients. Conclusions: We observed differences in TME phenotype and immune cell composition before ICI between AR &amp; PR patients. The TME change from immune-enriched to desert and cell composition change of increased M2 macrophages and decreased memory B and resting CD4+ T cells after AR to ICI could be significant mechanisms of AR to ICI. Citation Format: Cheol Yong Joe, Yeong Hak Bang, Sehhoon Park, Hyun Ae Jung, Jong-Mu Sun, Yoon-La Choi, Jin Seok Ahn, Myung-Ju Ahn, Se-Hoon Lee. Comprehensive transcriptomic analysis of acquired resistance after immune-checkpoint inhibitors 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 6839.
Abstract 6873: Prognostic impact of squamous cell carcinoma antigen as a mediator of anti-inflammatory macrophage polarization in tumor microenvironment
Authors: Liyun Chen, Victoria Shi, Eric Liu, Jasmine Yang, Abhay Singh, Matthew Inkman, Jin Zhang, Julie Schwarz, Stephanie Markovina
Journal: Cancer Research (2024)

Abstract Squamous cell carcinoma antigen 1 (SCCA1) is a potential biomarker and prognostic indicator for many epithelial cancers including cervix, head and neck, breast, and lung. Cancer patients with high serum levels of SCCA commonly experience treatment resistance and recurrence. We analyze SCCA expression in correlation with tumor microenvironment from 66 human cervical tumor biopsies and find that high serum SCCA is associated with increased macrophage infiltration in tumors and poor overall survival. In a single cell RNAseq analysis of 8 cervical tumors, patients with high SCCA1 show increased immunosuppressive genes (C1QA, C1QC, APOE) and reduced MHC molecules (HLA-DR, HLA-DQA1) in their tumor associated macrophages (TAMs), corresponding to decreased expression of T-cell cytotoxic-associated genes (IFNG, GZMB, PRF1). Thus, we aim to understand the impact of elevated SCCA1 on macrophages and its role in shaping the immune response. Co-culture of peritoneal macrophages isolated from SCCA1-treated mice with T cells from syngeneic wild-type mice, showed significant suppression in T cell proliferation. Downregulation of antigen presentation molecules was also observed SCCA1-treated macrophages and resulted in impaired ability to induce T cell activation by peptide-pulsed macrophages. Compared with treatment-naïve mice, SCCA1-treated macrophages showed increased anti-inflammatory cytokine CCL22, IL10 and immunosuppression regulators ARG1, PD-L1 expression. Moreover, human monocyte-derived M2 macrophages treated with SCCA1 during the differentiation process demonstrated inhibition toward CD3/28-induced T cell proliferation, accompanied by enhanced expression of cytokines, IL10 and CCL18. We further found that targeting SCCA1 by small interfering RNA knockdown significantly reduced tumor growth and macrophage infiltration, resulting in improved T-cell antitumor immunity. Lastly, analysis of cervical cancer patients with chemoradiation therapy showed that patients with high SCCA are associated with increased exhaustion (LAG3, CTLA4) and decreased antitumor gene signature (GZMB, IFNG) during treatment. In summary, SCCA expression promotes immunosuppressive macrophage polarization and function, contributing to T cell exhaustion phenotype and poor treatment response. Citation Format: Liyun Chen, Victoria Shi, Eric Liu, Jasmine Yang, Abhay Singh, Matthew Inkman, Jin Zhang, Julie Schwarz, Stephanie Markovina. Prognostic impact of squamous cell carcinoma antigen as a mediator of anti-inflammatory macrophage polarization in tumor microenvironment [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 6873.
Abstract 4550: Synergistic combinations of lurbinectedin with ONC212 in pancreatic cancer
Authors: Tej Tummala, Ashley S. Sevilla Uruchurtu, Nicholas R. Liguori, E. Abbas, Christopher G. Azzoli, Wafik S. El-Deiry
Journal: Cancer Research (2024)

Abstract Pancreatic cancer is a devastating disease with a poor five-year survival rate of approximately 12%. Given the poor prognosis of the disease, there is urgent need for novel therapeutic regimens. Lurbinectedin is chemotherapeutic compound that stalls and degrades RNA Polymerase II after binding to guanine-rich sequences in the minor groove of DNA. This stalls transcription machinery and leads to single- and double- stranded breaks in DNA and subsequent apoptosis. Our group recently described lurbinectedin’s potency as both a single agent and combinatorial agent with irinotecan and 5-fluorouracil in pancreatic cancer cell lines. We also recently discovered a synergistic interaction between lurbinectedin and ONC201/TIC10, a novel compound that induces the TRAIL apoptotic pathway, in small cell lung cancer cell lines. Synergy was accompanied by an activation of p-Chk1 and the integrated stress response. We now demonstrate a synergistic combination of lurbinectedin and ONC212, an imipridone and chemical derivative of ONC201, results in highly efficient killing of pancreatic tumor cells at sub-nanomolar concentrations of lurbinectedin and sub-micromolar concentrations of ONC212. We hypothesize that the integrated stress response underlies lurbinectedin and ONC212 synergy. We further hypothesize a combination of lurbinectedin and ONC212 will sensitize the tumor cells to CD8+ T-cell killing, which will be examined via co-culture assays. Our results are developing insights into a novel combinatorial therapeutic regimen while investigating the molecular mechanisms underlying synergism. Citation Format: Tej Tummala, Ashley S. Sevilla Uruchurtu, Nicholas R. Liguori, E. Abbas, Christopher G. Azzoli, Wafik S. El-Deiry. Synergistic combinations of lurbinectedin with ONC212 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 4550.
Abstract 4788: Noninvasive longitudinal monitoring of residual disease in chemotherapy-treated colorectal cancer patients
Authors: Alison D. Tang, Rebecca Gupte, Victoria Cheung, Tao Qing, Austin Cauwels, Emily Leff, Kimberly Walter, Ehsan Tabari, Alex Lovejoy, Jimmy C. Lin
Journal: Cancer Research (2024)

Abstract Noninvasive monitoring of cancer shows great promise in assessing therapy response and improving patient outcomes. Recently, various groups have developed methods that detect circulating tumor DNA (ctDNA) in the plasma to measure minimal or molecular residual disease (MRD). Aberrant DNA methylation patterns are a hallmark of cancers, and robust signals can be detected by sensitive ctDNA assays. Here, we present a methylation-based approach for longitudinal monitoring of tumor burden that is tumor-naive, i.e., with no reliance on prior characterization of tumor molecular characteristics. We assess the effectiveness of our approach in a cohort of colorectal cancer (CRC) patients receiving chemotherapy with or without additional targeted agents. Longitudinal blood samples were collected from patients (n = 57) while on therapy, which averaged 4.9 months, for a total of 239 sample collection time points (median per patient = 5). Based on RECIST status, 16 patients were classified as complete responders (CR) at the end of treatment. We generated plasma cell free DNA-derived libraries for methylation sequencing targeting regions relevant to CRC. Next, we computed a disease burden score for each sample and related these scores to clinical response (CR vs. non-CR). We trained a classifier on an independent cohort of CRC and healthy donor plasma cfDNA samples, and used this classifier to check for residual disease at the end of treatment for each of our 57 patients. The classifier detected residual disease in only 3/16 CRs (19%) but 35/41 non-CRs (85%). Two of the non-CR patients were initially assessed as CRs at earlier time points. In both cases, our method successfully detected residual disease at or prior to the CR assessment and consistently showed residual disease in all follow up samples. This suggests improved sensitivity relative to RECIST and highlights the potential of using noninvasive blood tests for continuous monitoring of CRC patients receiving therapy. Citation Format: Alison D. Tang, Rebecca Gupte, Victoria Cheung, Tao Qing, Austin Cauwels, Emily Leff, Kimberly Walter, Ehsan Tabari, Alex Lovejoy, Jimmy C. Lin. Noninvasive longitudinal monitoring of residual disease in chemotherapy-treated colorectal cancer patients [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 4788.
Abstract 1113: USP18 impairs the sensitivity of radiotherapy for nasopharyngeal carcinoma by promoting the ubiquitination and nuclear translocation of TRIM29
Authors: Jia-Yi Lin, Wei-Wei Zhang, Qing-Jie Li, Xue-Liang Fang, Jun-Yan Li, Shi-Wei He, Ying-Qin Li, Jun Ma, Na Liu, Yin Zhao, Rui Guo
Journal: Cancer Research (2024)

Abstract Radiotherapy is the main and preferred treatment for nasopharyngeal carcinoma (NPC), owing to its high sensitivity to radiation. However, there are ~20% patients suffering from tumor recurrence. Accumulating evidences show that protein ubiquitination plays a vital role in radiation caused DNA damage response. Here, we identified that the deubiquitinase USP18 is highly expressed in NPC tissues, and inversely associated with radiosensitivity of NPC cells. USP18 interacts with TRIM29 and promotes its K27-linked ubiquitination independent of its deubiquitinase activity. Further investigation reveals that USP18 acts as a scaffold to recruit the E3 ubiquitin ligase TRIM21 to directly ubiquitinate TRIM29 at Lys307, thus promoting its oligomerization and nuclear translocation, and thereby facilitates the DNA damage repair of NPC cells after irradiation. Clinically, higher expression of USP18 indicates poor response to radiotherapy and worse prognosis in NPC patients. Our findings reveal the critical role of USP18 in regulating radiosensitivity, and targeting USP18-TRIM21-TRIM29 axis maybe a novel strategy to synergize with radiotherapy for NPC patients. Citation Format: Jia-Yi Lin, Wei-Wei Zhang, Qing-Jie Li, Xue-Liang Fang, Jun-Yan Li, Shi-Wei He, Ying-Qin Li, Jun Ma, Na Liu, Yin Zhao, Rui Guo. USP18 impairs the sensitivity of radiotherapy for nasopharyngeal carcinoma by promoting the ubiquitination and nuclear translocation of TRIM29 [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 1113.
Abstract 6844: Discovery of a novel sialic acid O-acetyltransferase in colon tissue
Authors: Bum Seok Lee, Ashley Cook, Maged Zeineldin, Surojit Sur, Laura Dobbyn, Maria Popoli, Sana Khalili, Bert Vogelstein, Nickolas Papadopoulos, Shibin Zhou, Chetan Bettegowda, Phillip Buckhaults, Tatianna Larman, Kathy Gabrielson, Kenneth W. Kinzler, Nicolas Wyhs
Journal: Cancer Research (2024)

Abstract Sialic acids have critical functions relating to host-pathogenic interactions and the immune microenvironment. Subsequent post-translational O-acetyl modifications add an extra layer of control by modulating many of these interactions in both normal and transformed colorectal cells. The processes through which this modification is added to sialic acids are not completely understood. To date only one gene, CASD1, has been identified to encode a sialic acid O-acetyltransferase in human cells. We used whole-genome sequencing on normal human colon tissue to identify a haplotype strongly associated with colorectal sialic acid O-acetylation, as determined by histopathological mPAS staining. Only SNP’s of a single candidate gene within the haplotype correlated perfectly in a 91-sample validation set. CRISPR-Cas9 editing of this gene in 2D cell line and 3D normal colon organoid models yielded changes to modified sialic acid levels. These findings suggest that this candidate gene functions as a novel sialic acid O-acetyltransferase in colorectal tissue and could have implications as a diagnostic tool for patients with inflammatory diseases of the bowel or as an indicator for therapeutic targets in cancer. Citation Format: Bum Seok Lee, Ashley Cook, Maged Zeineldin, Surojit Sur, Laura Dobbyn, Maria Popoli, Sana Khalili, Bert Vogelstein, Nickolas Papadopoulos, Shibin Zhou, Chetan Bettegowda, Phillip Buckhaults, Tatianna Larman, Kathy Gabrielson, Kenneth W. Kinzler, Nicolas Wyhs. Discovery of a novel sialic acid O-acetyltransferase in colon tissue [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 6844.
Abstract 1829: Brusatol overcomes tyrosine kinase inhibitors resistance in myeloid leukemia cells by inhibiting translation of fast turnover protein cyclin D1 and Mcl-1
Authors: Huiming Hua, Ying Yang, Guangfuxin Lin, Jingyi Zhang, Samuel Waxman, Yongkui Jing
Journal: Cancer Research (2024)

Abstract Myeloid leukemia is characterized with fast proliferation and apoptosis evasion, which are controlled by mutant or activated tyrosine kinase signalings. Tyrosine kinase inhibitors (TKI) targeting BCR-ABL in chronic myeloid leukemia (CML) and FLT3-ITD in acute myeloid leukemia (AML) significantly improved the therapy, but not cure, due to the general resistance. Overactivated mTOR protein translation pathway is believed to be one of the mechanisms causing resistance and that targeting protein translation should be one effective approach to overcome resistance. Brusatol is a quassinoid extracted from the fruit of Brucea javanica and an inhibitor of protein translation. We tested its antiproliferation and apoptosis induction in a variety of AML and CML cell lines as well as in TKI resistant cell lines. Brusatol effectively inhibits the growth of seven leukemia cell lines with GI50 values less than 20 nM. Brusatol induces apoptosis in AML cell lines and induces G0/G1 phase arrest in CML cell lines. Brusatol decreases the levels of fast turnover protein cyclin D1 and Mcl-1. In FLT3-ITD inhibitor sorafenib resistant MOLM-13/Sor cell line brusatol exhibits similar growth inhibition and apoptosis induction with the parental MOLM-13 cells, associated with inhibition of Mcl-1 and FLT3-ITD proteins. In BCR-ABL inhibitor imatinib resistant K562/STI cell line brusatol is effective as in parental K562 cells, associated with inhibition of cyclin D1 and BCR-ABL proteins. Brusatol at 2 mg/kg effectively inhibit tumor growth of K562 xenografts without causing toxicity to normal organs. These data indicate that brusatol inhibits oncogenic protein translation and has potential to be used to treat TKI resistant leukemia. Citation Format: Huiming Hua, Ying Yang, Guangfuxin Lin, Jingyi Zhang, Samuel Waxman, Yongkui Jing. Brusatol overcomes tyrosine kinase inhibitors resistance in myeloid leukemia cells by inhibiting translation of fast turnover protein cyclin D1 and Mcl-1 [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 1829.
Abstract 1821: Conessine inhibits cell proliferation, migration and invasion, and induces apoptosis in liver cancer cells
Authors: Chia-Yang Li, Yu-Sheng Lin
Journal: Cancer Research (2024)

Abstract Cancer-related deaths from hepatocellular carcinoma (HCC) rank first worldwide. Although many attempts have been made to treat HCC, the survival rate remains unsatisfactory. Many plants from the family Apocynaceae, such as Holarrhena floribunda, contain conessine, a steroidal alkaloid. Several studies have indicated that conessine acts as an antihistamine with cancer therapy and antimicrobial resistance, but it hasn't been tested for its anti-cancer activity against liver cancer. Our study aimed to investigate the anticancer properties of conessine against liver cancer. We tested the effects of conessine on cell proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) markers using both Huh7 and Mahlavu cells. Our experimental results indicated that conessine inhibited cell proliferation, migration, motility, and invasion in Huh7 and Mahlavu cells. Results of Western blot analysis showed that conessine induced apoptosis and EMT in liver cancer cells. Taken together, our results demonstrated that conessine exhibits anticancer activity in liver cancer through suppressing cell proliferation, migration, and invasion, and inducing apoptosis, suggesting it may have benefits for liver cancer treatment. Citation Format: Chia-Yang Li, Yu-Sheng Lin. Conessine inhibits cell proliferation, migration and invasion, and induces apoptosis in liver cancer 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 1821.
Abstract 6824: Secretion of MAGE-A3 and MAGE-A4 in cell lines and lung cancer
Authors: Bailey Gilmore, Dehe Kong, Rachel Gonzalez, Jina Yom, Andy Han, Tianli Qu, Alex Strom, Xiaoxiao Zhao, Eden Zewdu, Hailey Guo, Zhaoying Guo, Ranran Zhang, Xiaomin Hu, Qi Ren, Xuan Liu, Wei Fu
Journal: Cancer Research (2024)

Abstract Melanoma-associated antigen gene A (MAGE-A) family of proteins have previously been shown to express in a variety of tumors, having different roles in cancer pathogenesis. MAGE-A3 and MAGE-A4 have both been shown to inhibit the p53 pathway which leads increased cell growth by stopping apoptosis. Both of these proteins have been associated with cancer progression and poor prognosis. In our studies, we have evaluated multiple MAGE-A3 and MAGE-A4 antibodies using CytoSections. While previous research had only pointed to these proteins being intracellular, our overexpression studies in the development of CytoSections indicated that some MAGE-A proteins were secreted. In this study, ELISA binding assays corroborated that MAGE-A3 and MAGE-A4 were secreted from cells overexpressing these proteins, and serum MAGE-A4 was detected in 24% of lung cancer patients. Flow cytometry data was then collected to see that exogenous MAGE-A proteins were binding to cells in a pattern consistent with secretion data from IHC experiments. Variants of MAGE-A4, differing by only a handful of amino acids, showed very different levels of secretion from one another. MAGE-A3 and MAGE-A6 share 95% homology and were also extremely different in secretion shown between IHC, flow cytometry, and ELISA. This study validates that certain members of the MAGE-A family are secreted from cells. Citation Format: Bailey Gilmore, Dehe Kong, Rachel Gonzalez, Jina Yom, Andy Han, Tianli Qu, Alex Strom, Xiaoxiao Zhao, Eden Zewdu, Hailey Guo, Zhaoying Guo, Ranran Zhang, Xiaomin Hu, Qi Ren, Xuan Liu, Wei Fu. Secretion of MAGE-A3 and MAGE-A4 in cell lines and 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 6824.