tbuckley/cabot-search huggingface dataset:
Abstract 4970: Prognostic role of CD112R, PD-1 and Ki67 expression in CD8+cytotoxic T cells in colorectal cancer
Authors: Ronald Simon, Niclas Christian Blessin, Tim Mandelkow, Elena Bady, Claudia Hube-Magg, Guido Sauter, Maximilian Lennartz, Christoph Fraune, Sören A. Weidemann, Katharina Möller, Franziska Büscheck
Journal: Cancer Research (2020)

Abstract Expression of inhibitory immune checkpoint receptors such as CD112R (Poliovirus Receptor-Related Immunoglobulin Domain-Containing Protein, PVRIG) and PD-1 on CD8+ lymphocytes are considered to indicate an “exhausted” stage of T cell activation while Ki67 protein expression in these cells is viewed as sign of activity or expansion. To assess the prognostic impact of the clinical impact of CD112R, PD-1, and Ki67 expression of CD8+ lymphocytes, expression of these proteins was analyzed by fluorescent multiplex immunohistochemistry on a tissue microarray containing 384 colorectal cancers with clinical follow-up data. An elevated fraction of CD8+Ki67+ cells was linked to the absence of nodal metastasis and longer survival in these tumors (p≤0.0039 each). CD112R and PD-1 expression was detected at variable intensity levels and were separately quantitated in both ki67+ (expanding) and Ki67 negative (non-expanding) CD8+ cytotoxic lymphocytes. Elevated PD-1 expression in CD8+ T cells was associated with an absence of nodal metastasis (p=0.004) and longer overall survival in all CD8+ cells (p=0.005). This association was more evident in the subset of expanding (p&amp;lt;0.0001) than in non-expanding (p=0.034) cytotoxic T cells. Elevated CD112R expression level in CD8+ T cells were linked to a low tumor grade (p=0.048), absence of nodal metastasis (p=0.023) and a prolonged overall survival (p=0.041) but these associations were not retained in subgroups of either expanding or non-expanding CD8+ cells. Patients with an elevated fraction of CD8+ki67+CD112R+PD-1+cells exhibited a particularly good prognosis. In conclusion, our data reveal that “exhausted” CD112R+/ PD-1+CD8+ cytotoxic T lymphocytes are able to expand (ki67+). This observation in combination with the good prognosis of cancers with high number of expanding exhausted cells argues for retained cytotoxic activity of CD112R+/ PD-1+ CD8+ T lymphocytes. Citation Format: Ronald Simon, Niclas Christian Blessin, Tim Mandelkow, Elena Bady, Claudia Hube-Magg, Guido Sauter, Maximilian Lennartz, Christoph Fraune, Sören A. Weidemann, Katharina Möller, Franziska Büscheck. Prognostic role of CD112R, PD-1 and Ki67 expression in CD8+cytotoxic T cells in colorectal cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4970.
Abstract 1209: The association between the cell cycle control pathway and pediatric germ cell tumors
Authors: Aubrey K. Hubbard, Nathan Pankratz, Spencer T. Kelley, John J. Meredith, Jenny N. Poynter
Journal: Cancer Research (2020)

Abstract Pediatric germ cell tumors (GCTs) account for approximately 6% of childhood cancers. GCTs are heterogeneous but are grouped together due to a common cell of origin, the primordial germ cell. GCTs are predicted to have high heritability, therefore, genetic association studies are paramount in understanding GCT etiology. Genome-wide association (GWA) studies commonly ignore the aggregate effect of SNPs/genes with weaker individual associations. Pathway-based approaches provide the opportunity to interrogate joint SNP effects in pathways of interest. The cell cycle control pathway is a plausible candidate pathway given the knowledge that alterations in the the mitotic-meiotic switch may lead to genetic instability and initiate GCT development. In this analysis we evaluated a set of 94 genes associated with cell cycle control using data from a case-parent triad study of pediatric GCT. Genes involved in cell cycle control were identified using Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. We also included additional genes based on reports in the literature suggesting a role in cell cycle control in GCTs, including STRA832, 33, CYP26B134, CKS1B35, and E2F636. Variants within 25,000 base pairs upstream or downstream of the gene were selected for inclusion resulting in a total of 2,846 SNPs included in the analysis. Genotyping data were generated using the Illumina HumanCore Exome Array for 867 GCT cases and their unaffected parents. Preliminary results evaluating individual effects of SNPs in the pathway were conducted using the transmission disequilibrium test (TDT). We did not observe any individual SNP associations that reached genome-wide significance; however, suggestive associations were observed for SNPs located in CDKN2C (p=0.000208), MCM7 (p=0.000787), RB1 (p=0.000798), RBL2 (p=0.00250) and TP53 (p=0.00257). Replication of these findings will be conducted using data from a record linkage case-control study from neonatal biobanks in California and Michigan (N=837 cases and 1057 controls). In addition, we will utilize pathway-based approaches to jointly evaluate the effects of genes in this pathway, including Gene Set Enrichment Analysis for Genome wide association study (i-GSEA4GWAS), MetXcan for functional significance, and Family-based rare-variant association analysis (PedGene). In conclusion, our results suggest that genes within the cell-cycle control pathway play a role in the etiology of pediatric GCT. Citation Format: Aubrey K. Hubbard, Nathan Pankratz, Spencer T. Kelley, John J. Meredith, Jenny N. Poynter. The association between the cell cycle control pathway and pediatric germ cell tumors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1209.
Abstract 6527: Targeting glycosylated PD-1 induces potent anti-tumor immunity
Authors: Yuhan Wang, Linlin Sun, Riyao Yang, Jielin Liu, Yufan Qiu, Jennifer L. Hsu, Jong-ho Cha, Li-Chuan Chan, Jung-Mao Hsu, Heng-Huan Lee, Yun-Ju Lai, Kay-Hooi Khoo, Ezra M Chung, Chia-Wei Li, Yong-Soo Kim, Andrew H Park, Yi Yang, Stephen S. Yoo, Mien-Chie Hung
Journal: Cancer Research (2020)

Abstract Immunotherapy targeting programmed cell death protein 1 (PD-1) and programmed cell death 1 ligand 1 (PD-L1) immune checkpoints represents a major breakthrough in cancer treatment. PD-1 is an inhibitory receptor expressed on the surface of activated T cells that dampens T-cell receptor (TCR)/CD28 signaling by engaging with its ligand PD-L1 expressed on cancer cells. Despite the clinical success of PD-1 blockade using monoclonal antibodies, most patients do not show promising results, and the underlying regulatory mechanisms of PD-1 remain incompletely defined. Here, we showed that PD-1 is extensively N-glycosylated in T cells, and the intensities of its specific glycoforms are altered upon TCR activation. Glycosylation is critical for maintaining PD-1 protein stability and cell surface localization. Importantly, the glycosylation of PD-1, especially at the N58 site, is essential for mediating the interaction with PD-L1. A monoclonal antibody that specifically targets glycosylated PD-1, STM418, exhibits higher binding affinity to PD-1 than FDA-approved PD-1 antibodies, potently inhibits PD-L1/PD-1 binding, and enhances anti-tumor immunity. Our findings provide novel insights into the functional significance of PD-1 glycosylation and offer a rationale for targeting glycosylated PD-1 as a potential strategy for immunotherapy. Citation Format: Yuhan Wang, Linlin Sun, Riyao Yang, Jielin Liu, Yufan Qiu, Jennifer L. Hsu, Jong-ho Cha, Li-Chuan Chan, Jung-Mao Hsu, Heng-Huan Lee, Yun-Ju Lai, Kay-Hooi Khoo, Ezra M Chung, Chia-Wei Li, Yong-Soo Kim, Andrew H Park, Yi Yang, Stephen S. Yoo, Mien-Chie Hung. Targeting glycosylated PD-1 induces potent anti-tumor immunity [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6527.
Abstract 4374: CE+BZA combination therapy decreases breast cancer outgrowth in part through activation of the AHR pathway
Authors: Anna G. Dembo, Emily S. Aledort, Geoffrey L. Greene
Journal: Cancer Research (2020)

Abstract Menopause occurs in all women, usually between the ages of 45 and 55. As a result of menopause, women often experience undesirable vasomotor symptoms, which can be alleviated by hormone replacement therapy (HRT). The Women's Health Initiative (WHI) trial concluded that PremPro, a HRT formulation that combines conjugated equine estrogens (CE) with medroxyprogesterone acetate, increases the risk of breast cancer. Over the years, the number of women taking HRT has dramatically decreased due to the perceived risk based largely on the results of the WHI trial. Follow-up studies suggest that breast cancer cases from PremPro treatment were primarily due to the outgrowth of occult tumors, not the formation of new disease. Duavee, a more recent form of HRT that combines CE and bazedoxifene (BZA), a selective estrogen receptor modulator (SERM) and degrader (SERD), has been approved by the FDA for treatment of moderate to severe hot flashes and to reduce the risk of osteoporosis. More importantly, this CE+BZA mixture not only relieves symptoms associated with menopause, but it also does not stimulate the breast or uterus. Several preclinical studies suggest that CE+BZA might be protective in the breast, however the mechanism of action of this new combination therapy is not known. Our goal, therefore, was to elucidate the underlying molecular mechanisms by which CE+BZA differentially affects estrogen receptor alpha (ERα) action in the mammary gland. Pathway analysis from RNA-sequencing revealed Aryl Hydrocarbon Receptor (AHR) signaling as the top canonical pathway affected by treatment with CE+BZA. Previous studies reported that 4-hydroxytamoxifen, a metabolite of the SERM tamoxifen, was able to activate the AHR pathway. In our study we determined that BZA treatment activated the AHR pathway in both ERα-positive and ERα-negative cell lines. BZA increased expression of aryl hydrocarbon receptor repressor (AHRR) in cell lines and increased expression of two AHR pathway members, CYP1A1 and CYP1B1, in tumors of estrogen-sensitive polyoma middle T antigen (PyMT) mice. AHRR has been reported to act as a tumor suppressor in breast cancer; therefore activation of AHR by BZA in women taking CE+BZA combination therapy might be one mechanism by which outgrowth of occult tumors is decreased. Further evaluation of the role of AHR in breast cancer is necessary to improve our understanding of CE+BZA action. Citation Format: Anna G. Dembo, Emily S. Aledort, Geoffrey L. Greene. CE+BZA combination therapy decreases breast cancer outgrowth in part through activation of the AHR pathway [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4374.
Abstract 1572: Single cell sequencing reveals the microenvironment network in multifocal pulmonary nodules
Authors: Dongcheng Liu, Pan Pan, Shixuan Li, Zhiqiang Cheng, Guangsuo Wang, Chang Zou
Journal: Cancer Research (2020)

Abstract Tumor microenvironment plays an important role in tumorigenesis in cancer development, however, little is known about its heterogeneity and evolution progression during early stage of lung cancer. In this study, single cell sequencing was applied to uncover the transcriptome in the microenvironment and the complex ecosystem of stromal cells in pulmonary nodules including atypical adenomatous hyperplasia (AAH) adenocarcinoma in situ (AIS), invasive adenocarcinoma (MIA) and invasive adenocarcinoma (IA). Although the expression or mutation of driver genes were detected in different stage of pulmonary lesion tissues that might contribute to the development of lung cancer, tumor environment including immune system are found to be important for the progression of tumorigeneses. This study provided evidence that the different evolutionary selection and microenvironment network in multifocal pulmonary nodules in the same individual resulted in various cancer progression stages. To our knowledge, this study first provides an overview of the genetic basis and tumor environment of human lung nodule by single-cell sequencing. Keywords: Single cell sequencing; heterogeneous; microenvironment; multifocal pulmonary nodules Citation Format: Dongcheng Liu, Pan Pan, Shixuan Li, Zhiqiang Cheng, Guangsuo Wang, Chang Zou. Single cell sequencing reveals the microenvironment network in multifocal pulmonary nodules [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1572.
Abstract 2847: Multiplex bead array approach for quantitative profiling of 95 cancer-immunity biomarkers in breast cancer
Authors: Wen-Rong Lie, Alexander Davies, Danielle Pepin, Michael Godeny
Journal: Cancer Research (2020)

Abstract Immune regulators, including immune checkpoint proteins and cytokines/chemokines, have an emerging role as both disease/treatment biomarkers and targeted agents in cancer therapies. To contribute to the understanding of the roles of these immune regulators in cancer, we have developed 3 new Luminex-based multiplex immunoassay panels, a 48-plex human cytokine/chemokine panel, a 17-plex human immune checkpoint protein panel, and a 30-plex human immune checkpoint protein panel, to simultaneously quantitate the expression levels of 95 key immune regulator proteins in biofluids or cell/tissue homogenates. Here we report the quantitative profiles of these 95 immune regulators in 4 types of breast cancer samples: cancer versus healthy control serum samples, the lysates from breast cancer tumor biopsies versus the adjacent normal tissues, the conditioned media and lysates from the established breast cancer cell lines, and breast cancer cell-derived exosomes. Analysis of the circulating immune protein signatures generated from this multiplex approach reveals an elevated level of IL-6, IL-27, M-CSF, MDC, MIG, sCD27, sTIM3, sCD40, Galectin-3, Galectin-1, FGL-1, BAFF and low level of EGF and sCD40L in breast cancer serum samples compared to the healthy serum controls. The expression profiling of tumor and adjacent normal tissues from 3 patients with metastatic breast cancer revealed differential expression of multiple protein markers including IL-6, IL-8, MIG, IL-1ra, IL-18, IP-10, MCP-1, MIP-1b, VEGF, BTLA, HVEM, CTLA-4, CD40, TLR-2, Siglec-9, CD25, Granzyme B, APRIL, BAFF, Nectin-2, Nectin-4, E-cadherin, and IDO-1 in the matched lysates. We performed similar analysis using cultured breast tumor cells. In these samples we identified markers with significantly altered expression in conditioned media, cell lysates, and tumor cell-derived exosomes from MCF10CA1d tumor cells versus MCF-10A non-tumorigenic mammary epithelial cells as well as triple negative HMT-3522 T4-2 and MDA-MB-231 breast cancer cells. Altogether, our results suggest Luminex-based profiling allows for sensitive and versatile multiplexed analysis of stimulating and inhibitory immune mediators in circulation, tissues, and cell lines which will assist in the discovery of biomarkers and therapeutic targets for cancer interventions. Citation Format: Wen-Rong Lie, Alexander Davies, Danielle Pepin, Michael Godeny. Multiplex bead array approach for quantitative profiling of 95 cancer-immunity biomarkers in breast cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2847.
Abstract 720: Analysis of circulating tumor DNA after neoadjuvant therapy to predict disease relapse in patients with stage II-III breast cancer
Authors: Po-Han Lin, Sung-Sheng Kuo, Chiun-Sheng Huang
Journal: Cancer Research (2020)

Abstract The therapeutic efficacy of neoadjuvant chemotherapy for patients with breast cancer is usually assessed by the reduction of tumor size and lymph nodes. The pathologic complete response (pCR) is considered as a marker related to good prognosis. However, patients who can achieve pCR is a minor population, and pCR may be not a robust marker predicting prognosis in patients with ER-positive breast cancer. Additional markers allowing the assessment of prognosis is needed. Circulating tumor DNA (ctDNA) has been proved as a marker to detect disease progression in metastatic breast cancer and predict relapse in patients after resection of breast cancer. Therefore, we would like to assess the value of ctDNA in breast cancer patients receiving neoadjuvant therapy. The ctDNA was collected before and after completion of the neoadjuvant chemotherapy (Tend). The presence of ctDNA was detected by ultra-deep targeted next-generation sequencing. We enrolled 82 patients and 62 patients were found to have ctDNA as the biomarkers. The presence of ctDNA included nonsynonymous variants and copy number variations in TP53, PIK3CA, HER2, CDH1, PTEN, S100A, CCND1 and c-MYC. Among the 62 patients, there were 24 patients with hormone receptor (+)/Her2(-), 20 with Her2(+) and 18 with triple-negative breast cancer (TNBC). Pathologic complete response (pCR) occurred in 9 patients, partial response in 32 patients and stable/progression in 21 patients, according to the RECIST 1.1 criteria. Univariate analysis showed tumor reduction&amp;gt;50% (p=0.032), number of metastatic lymph node (p=0.039), and status of ctDNA at Tend (p&amp;lt;0.001) were significantly associated with disease-free survival (DFS). The 5-year DFS of patients with undetectable ctDNA at Tend (74.0%, 95% confidence interval (CI) range 98%-50%) was significantly superior to those with detected ctDNA (16.8%, 95% CI range 36.1%-0%). Multivariate analysis revealed that status of ctDNA at Tend was the only one independent factor predicting relapse (hazard ratio 7.74, 95% CI 2.81-21.35). Two patients had pCR and were found to have alterations of ctDNA at Tend; one with TNBC had distant metastases at 6 months after mastectomy and the other with Her2 (+) breast cancer had brain metastasis at the end of adjuvant trastuzumab treatment. Therefore, we concluded that the presence of ctDNA at the end of the neoadjuvant chemotherapy was a poor prognostic factor predicting relapse in patients with stage II-III breast cancer. Citation Format: Po-Han Lin, Sung-Sheng Kuo, Chiun-Sheng Huang. Analysis of circulating tumor DNA after neoadjuvant therapy to predict disease relapse in patients with stage II-III breast cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 720.
The Apelin–Apelin Receptor Axis Triggers Cholangiocyte Proliferation and Liver Fibrosis During Mouse Models of Cholestasis
Authors: Lixian Chen, Tianhao Zhou, Tori White, April O'Brien, Sanjukta Chakraborty, Suthat Liangpunsakul, Zhihong Yang, Lindsey Kennedy, Romil Saxena, Chaodong Wu, Fanyin Meng, Qiaobing Huang, Heather Francis, Gianfranco Alpini, Shannon Glaser
Journal: Hepatology (2020)

Background and Aims Apelin (APLN) is the endogenous ligand of its G protein–coupled receptor, apelin receptor (APJ). APLN serum levels are increased in human liver diseases. We evaluated whether the APLN–APJ axis regulates ductular reaction and liver fibrosis during cholestasis. Approach and Results We measured the expression of APLN and APJ and serum APLN levels in human primary sclerosing cholangitis (PSC) samples. Following bile duct ligation (BDL) or sham surgery, male wild‐type (WT) mice were treated with ML221 (APJ antagonist) or saline for 1 week. WT and APLN −/− mice underwent BDL or sham surgery for 1 week. Multidrug resistance gene 2 knockout (Mdr2 −/− ) mice were treated with ML221 for 1 week. APLN levels were measured in serum and cholangiocyte supernatants, and cholangiocyte proliferation/senescence and liver inflammation, fibrosis, and angiogenesis were measured in liver tissues. The regulatory mechanisms of APLN–APJ in (1) biliary damage and liver fibrosis were examined in human intrahepatic biliary epithelial cells (HIBEpiCs) treated with APLN and (2) hepatic stellate cell (HSC) activation in APLN‐treated human HSC lines (HHSteCs). APLN serum levels and biliary expression of APLN and APJ increased in PSC samples. APLN levels were higher in serum and cholangiocyte supernatants from BDL and Mdr2 −/− mice. ML221 treatment or APLN −/− reduced BDL‐induced and Mdr2 −/− ‐induced cholangiocyte proliferation/senescence, liver inflammation, fibrosis, and angiogenesis. In vitro , APLN induced HIBEpiC proliferation, increased nicotinamide adenine dinucleotide phosphate oxidase 4 (Nox4) expression, reactive oxygen species (ROS) generation, and extracellular signal–regulated kinase (ERK) phosphorylation. Pretreatment of HIBEpiCs with ML221, diphenyleneiodonium chloride (Nox4 inhibitor), N ‐acetyl‐cysteine (NAC, ROS inhibitor), or PD98059 (ERK inhibitor) reduced APLN‐induced cholangiocyte proliferation. Activation of HHSteCs was induced by APLN but reduced by NAC. Conclusions The APLN–APJ axis induces cholangiocyte proliferation through Nox4/ROS/ERK‐dependent signaling and HSC activation through intracellular ROS. Modulation of the APLN–APJ axis may be important for managing cholangiopathies.
Abstract 6625: Cancer neoepitope identification in soluble HLA from patient plasma
Authors: Julie M. Rumble, Michael Pisano, Richard Jones, Michael Ford
Journal: Cancer Research (2020)

Abstract The roles of the Major Histocompatibility Complexes (MHC) in anti-cancer immunity are well established. Cytotoxic immune cells can recognize MHC presentation of unique peptides from altered proteins on the surface of tumor cells (tumor neoantigens) or the downregulation of MHC itself and kill the affected cells. One of the hallmarks of cancer progression is the evasion of anti-tumor immunity by various mechanisms, including the upregulation of checkpoint proteins. Checkpoint inhibitors, which have recently seen dramatic success in the clinic in some cancers, act by inducing potent immune responses to tumor neoantigens. In addition, the promise of personalized medicine lies in the theoretical ability to teach the immune system through vaccination to recognize and kill tumor cells bearing MHC-presented neoantigens. Aside from MHC on cell surfaces, the presence of soluble MHC (sMHC) has been shown in a variety of bodily fluids, including blood. Soluble MHC may be an important component of the tumor arsenal for inhibiting anti-tumor immune responses. The precise function of sMHC may be disease-dependent, but it has been postulated to play an inhibitory role, presumably through signaling cognate TCRs in the absence of a cellular signal (signal 2). Presence of sMHC carrying cancer-associated neoantigens could predict success of vaccination therapy or checkpoint therapy. Furthermore, sMHC-associated peptides could help to identify neoantigens that have already induced T cell anergy and would hence not be good targets. Here, data are presented describing the plasma immunopeptidome of advanced non small-cell lung cancer subjects under a variety of treatment paradigms. Citation Format: Julie M. Rumble, Michael Pisano, Richard Jones, Michael Ford. Cancer neoepitope identification in soluble HLA from patient plasma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6625.