Trevor Clancy

• Sverchkova, Angelina; Burkholz, Scott; Rubsamen, Reid; Stratford, Richard & Clancy, Trevor (2024). Integrative HLA typing of tumor and adjacent normal tissue can reveal insights into the tumor immune response. BMC Medical Genomics. 17(1). doi: 10.1186/s12920-024-01808-8. Fulltekst i vitenarkiv Vis sammendrag

  Background The HLA complex is the most polymorphic region of the human genome, and its improved characterization can help us understand the genetics of human disease as well as the interplay between cancer and the immune system. The main function of HLA genes is to recognize “non-self” antigens and to present them on the cell surface to T cells, which instigate an immune response toward infected or transformed cells. While sequence variation in the antigen-binding groove of HLA may modulate the repertoire of immunogenic antigens presented to T cells, alterations in HLA expression can significantly influence the immune response to pathogens and cancer. Methods RNA sequencing was used here to accurately genotype the HLA region and quantify and compare the level of allele-specific HLA expression in tumors and patient-matched adjacent normal tissue. The computational approach utilized in the study types classical and non-classical Class I and Class II HLA alleles from RNA-seq while simultaneously quantifying allele-specific or personalized HLA expression. The strategy also uses RNA-seq data to infer immune cell infiltration into tumors and the corresponding immune cell composition of matched normal tissue, to reveal potential insights related to T cell and NK cell interactions with tumor HLA alleles. Results The genotyping method outperforms existing RNA-seq-based HLA typing tools for Class II HLA genotyping. Further, we demonstrate its potential for studying tumor-immune interactions by applying the method to tumor samples from two different subtypes of breast cancer and their matched normal breast tissue controls. Conclusions The integrative RNA-seq-based HLA typing approach described in the study, coupled with HLA expression analysis, neoantigen prediction and immune cell infiltration, may help increase our understanding of the interplay between a patient’s tumor and immune system; and provide further insights into the immune mechanisms that determine a positive or negative outcome following treatment with immunotherapy such as checkpoint blockade.

• Netskar, Herman Krogstad; Pfefferle, Aline; Goodridge, Jodie; Sohlberg, Ebba; Dufva, Olli & Teichmann, Sarah A [Vis alle 12 forfattere av denne artikkelen] (2024). Pan-cancer profiling of tumor-infiltrating natural killer cells through transcriptional reference mapping. Nature Immunology. ISSN 1529-2908. 25, s. 1445–1459. doi: 10.1038/s41590-024-01884-z. Fulltekst i vitenarkiv Vis sammendrag

  The functional diversity of natural killer (NK) cell repertoires stems from differentiation, homeostatic, receptor–ligand interactions and adaptive-like responses to viral infections. In the present study, we generated a single-cell transcriptional reference map of healthy human blood- and tissue-derived NK cells, with temporal resolution and fate-specific expression of gene-regulatory networks defining NK cell differentiation. Transfer learning facilitated incorporation of tumor-infiltrating NK cell transcriptomes (39 datasets, 7 solid tumors, 427 patients) into the reference map to analyze tumor microenvironment (TME)-induced perturbations. Of the six functionally distinct NK cell states identified, a dysfunctional stressed CD56bright state susceptible to TME-induced immunosuppression and a cytotoxic TME-resistant effector CD56dim state were commonly enriched across tumor types, the ratio of which was predictive of patient outcome in malignant melanoma and osteosarcoma. This resource may inform the design of new NK cell therapies and can be extended through transfer learning to interrogate new datasets from experimental perturbations or disease conditions.

• Ellingsen, Espen Basmo; O'Day, Steven; Mezheyeuski, Artur; Gromadka, Agnieszka; Clancy, Trevor & Kristedja, Timothy S. [Vis alle 8 forfattere av denne artikkelen] (2023). Clinical Activity of Combined Telomerase Vaccination and Pembrolizumab in Advanced Melanoma: Results from a Phase I Trial. Clinical Cancer Research. ISSN 1078-0432. 29(16), s. 3026–3036. doi: 10.1158/1078-0432.CCR-23-0416. Fulltekst i vitenarkiv Vis sammendrag

  Abstract Purpose: Cancer vaccines represent a novel treatment modality with a complementary mode of action addressing a crucial bottleneck for checkpoint inhibitor (CPI) efficacy. CPIs are expected to release brakes in T-cell responses elicited by vaccination, leading to more robust immune responses. Increased antitumor T-cell responses may confer increased antitumor activity in patients with less immunogenic tumors, a subgroup expected to achieve reduced benefit from CPIs alone. In this trial, a telomerase-based vaccine was combined with pembrolizumab to assess the safety and clinical activity in patients with melanoma. Patients and Methods: Thirty treatment-naïve patients with advanced melanoma were enrolled. Patients received intradermal injections of UV1 with adjuvant GM-CSF at two dose levels, and pembrolizumab according to the label. Blood samples were assessed for vaccine-induced T-cell responses, and tumor tissues were collected for translational analyses. The primary endpoint was safety, with secondary objectives including progression-free survival (PFS), overall survival (OS), and objective response rate (ORR). Results: The combination was considered safe and well-tolerated. Grade 3 adverse events were observed in 20% of patients, with no grade 4 or 5 adverse events reported. Vaccination-related adverse events were mostly mild injection site reactions. The median PFS was 18.9 months, and the 1- and 2-year OS rates were 86.7% and 73.3%, respectively. The ORR was 56.7%, with 33.3% achieving complete responses. Vaccine-induced immune responses were observed in evaluable patients, and inflammatory changes were detected in posttreatment biopsies. Conclusions: Encouraging safety and preliminary efficacy were observed. Randomized phase II trials are currently ongoing.

• Federico, Lorenzo; Malone, Brandon; Tennøe, Simen; Chaban, Viktoriia; Osen, Julie Røkke & Gainullin, Murat [Vis alle 13 forfattere av denne artikkelen] (2023). Experimental validation of immunogenic SARS-CoV-2 T cell epitopes identified by artificial intelligence. Frontiers in Immunology. 14:1265044, s. 1–14. doi: 10.3389/fimmu.2023.1265044. Fulltekst i vitenarkiv Vis sammendrag

  During the COVID-19 pandemic we utilized an AI-driven T cell epitope prediction tool, the NEC Immune Profiler (NIP) to scrutinize and predict regions of T cell immunogenicity (hotspots) from the entire SARS-CoV-2 viral proteome. These immunogenic regions offer potential for the development of universally protective T cell vaccine candidates. Here, we validated and characterized T cell responses to a set of minimal epitopes from these AI-identified universal hotspots. Utilizing a flow cytometry-based T cell activation-induced marker (AIM) assay, we identified 59 validated screening hits, of which 56% (33 peptides) have not been previously reported. Notably, we found that most of these novel epitopes were derived from the non-spike regions of SARS-CoV-2 (Orf1ab, Orf3a, and E). In addition, ex vivo stimulation with NIP-predicted peptides from the spike protein elicited CD8 + T cell response in PBMC isolated from most vaccinated donors. Our data confirm the predictive accuracy of AI platforms modelling bona fide immunogenicity and provide a novel framework for the evaluation of vaccine-induced T cell responses.

• Lagran, Irantzu Anzar Martinez de; Malone, Brandon; Samarakoon, Pubudu Saneth; Vardaxis, Ioannis; Simovski, Boris & Fontenelle, Hugues [Vis alle 13 forfattere av denne artikkelen] (2023). The interplay between neoantigens and immune cells in sarcomas treated with checkpoint inhibition. Frontiers in Immunology. 14. doi: 10.3389/fimmu.2023.1226445. Fulltekst i vitenarkiv Vis sammendrag

  Introduction: Sarcomas are comprised of diverse bone and connective tissue tumors with few effective therapeutic options for locally advanced unresectable and/or metastatic disease. Recent advances in immunotherapy, in particular immune checkpoint inhibition (ICI), have shown promising outcomes in several cancer indications. Unfortunately, ICI therapy has provided only modest clinical responses and seems moderately effective in a subset of the diverse subtypes. Methods: To explore the immune parameters governing ICI therapy resistance or immune escape, we performed whole exome sequencing (WES) on tumors and their matched normal blood, in addition to RNA-seq from tumors of 31 sarcoma patients treated with pembrolizumab. We used advanced computational methods to investigate key immune properties, such as neoantigens and immune cell composition in the tumor microenvironment (TME). Results: A multifactorial analysis suggested that expression of high quality neoantigens in the context of specific immune cells in the TME are key prognostic markers of progression-free survival (PFS). The presence of several types of immune cells, including T cells, B cells and macrophages, in the TME were associated with improved PFS. Importantly, we also found the presence of both CD8+ T cells and neoantigens together was associated with improved survival compared to the presence of CD8+ T cells or neoantigens alone. Interestingly, this trend was not identified with the combined presence of CD8+ T cells and TMB; suggesting that a combined CD8+ T cell and neoantigen effect on PFS was important. Discussion: The outcome of this study may inform future trials that may lead to improved outcomes for sarcoma patients treated with ICI.

• Gainullin, Murat; Federico, Lorenzo; Osen, Julie Røkke; Chaban, Viktoriia; Kared, Hassen & Alirezaylavasani, Amin [Vis alle 18 forfattere av denne artikkelen] (2023). People who use drugs show no increase in pre-existing T-cell cross-reactivity toward SARS-CoV-2 but develop a normal polyfunctional T-cell response after standard mRNA vaccination. Frontiers in Immunology. 14:1235210, s. 1–13. doi: 10.3389/fimmu.2023.1235210. Fulltekst i vitenarkiv Vis sammendrag

  People who use drugs (PWUD) are at a high risk of contracting and developing severe coronavirus disease 2019 (COVID-19) and other infectious diseases due to their lifestyle, comorbidities, and the detrimental effects of opioids on cellular immunity. However, there is limited research on vaccine responses in PWUD, particularly regarding the role that T cells play in the immune response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Here, we show that before vaccination, PWUD did not exhibit an increased frequency of preexisting cross-reactive T cells to SARS-CoV-2 and that, despite the inhibitory effects that opioids have on T-cell immunity, standard vaccination can elicit robust polyfunctional CD4 + and CD8 + T-cell responses that were similar to those found in controls. Our findings indicate that vaccination stimulates an effective immune response in PWUD and highlight targeted vaccination as an essential public health instrument for the control of COVID-19 and other infectious diseases in this group of high-risk patients.

• Federico, Lorenzo; Tvedt, Tor Henrik Anderson; Gainullin, Murat; Osen, Julie Røkke; Chaban, Viktoriia & Lund, Kathrine Persgård [Vis alle 19 forfattere av denne artikkelen] (2023). Robust spike-specific CD4⁺ and CD8⁺ T cell responses in SARS-CoV-2 vaccinated hematopoietic cell transplantation recipients: a prospective, cohort study. Frontiers in Immunology. 14. doi: 10.3389/fimmu.2023.1210899. Fulltekst i vitenarkiv Vis sammendrag

  Poor overall survival of hematopoietic stem cell transplantation (HSCT) recipients who developed COVID-19 underlies the importance of SARS-CoV-2 vaccination. Previous studies of vaccine efficacy have reported weak humoral responses but conflicting results on T cell immunity. Here, we have examined the relationship between humoral and T cell response in 48 HSCT recipients who received two doses of Moderna’s mRNA-1273 or Pfizer/BioNTech’s BNT162b2 vaccines. Nearly all HSCT patients had robust T cell immunity regardless of protective humoral responses, with 18/48 (37%, IQR 8.679-5601 BAU/mL) displaying protective IgG anti-receptor binding domain (RBD) levels (>2000 BAU/mL). Flow cytometry analysis of activation induced markers (AIMs) revealed that 90% and 74% of HSCT patients showed reactivity towards immunodominant spike peptides in CD8 + and CD4 + T cells, respectively. The response rate increased to 90% for CD4 + T cells as well when we challenged the cells with a complete set of overlapping peptides spanning the entire spike protein. T cell response was detectable as early as 3 months after transplant, but only CD4 + T cell reactivity correlated with IgG anti-RBD level and time after transplantation. Boosting increased seroconversion rate, while only one patient developed COVID-19 requiring hospitalization. Our data suggest that HSCT recipients with poor serological responses were protected from severe COVID-19 by vaccine-induced T cell responses.

• Anzar, Irantzu; Samarakoon, Pubudu Saneth; Sverchkova, Angelina; Ellingsen, Espen Basmo; Gaudernack, Gustav & Stratford, Richard [Vis alle 7 forfattere av denne artikkelen] (2022). Personalized HLA typing leads to the discovery of novel HLA alleles and tumor-specific HLA variants. HLA. ISSN 2059-2302. Fulltekst i vitenarkiv
• Ellingsen, Espen Basmo; Bounova, Gergana; Kerzeli, Iliana; Anzar, Irantzu; Simnica, Donjete & Aamdal, Elin [Vis alle 14 forfattere av denne artikkelen] (2022). Characterization of the T cell receptor repertoire and melanoma tumor microenvironment upon combined treatment with ipilimumab and hTERT vaccination. Journal of Translational Medicine. 20(1). doi: 10.1186/s12967-022-03624-z. Fulltekst i vitenarkiv Vis sammendrag

  Background This clinical trial evaluated a novel telomerase-targeting therapeutic cancer vaccine, UV1, in combination with ipilimumab, in patients with metastatic melanoma. Translational research was conducted on patient-derived blood and tissue samples with the goal of elucidating the effects of treatment on the T cell receptor repertoire and tumor microenvironment. Methods The trial was an open-label, single-center phase I/IIa study. Eligible patients had unresectable metastatic melanoma. Patients received up to 9 UV1 vaccinations and four ipilimumab infusions. Clinical responses were assessed according to RECIST 1.1. Patients were followed up for progression-free survival (PFS) and overall survival (OS). Whole-exome and RNA sequencing, and multiplex immunofluorescence were performed on the biopsies. T cell receptor (TCR) sequencing was performed on the peripheral blood and tumor tissues. Results Twelve patients were enrolled in the study. Vaccine-specific immune responses were detected in 91% of evaluable patients. Clinical responses were observed in four patients. The mPFS was 6.7 months, and the mOS was 66.3 months. There was no association between baseline tumor mutational burden, neoantigen load, IFN-γ gene signature, tumor-infiltrating lymphocytes, and response to therapy. Tumor telomerase expression was confirmed in all available biopsies. Vaccine-enriched TCR clones were detected in blood and biopsy, and an increase in the tumor IFN-γ gene signature was detected in clinically responding patients. Conclusion Clinical responses were observed irrespective of established predictive biomarkers for checkpoint inhibitor efficacy, indicating an added benefit of the vaccine-induced T cells. The clinical and immunological read-out warrants further investigation of UV1 in combination with checkpoint inhibitors.

• Pfefferle, Aline; Jacobs, Benedikt Marcel; Netskar, Herman; Ask, Eivind Heggernes; Lorenz, Susanne & Clancy, Trevor [Vis alle 9 forfattere av denne artikkelen] (2019). Intra-lineage plasticity and functional reprogramming maintain natural killer cell repertoire diversity. Cell reports. 29(8), s. 2284–2294.e4. doi: 10.1016/j.celrep.2019.10.058. Fulltekst i vitenarkiv Vis sammendrag

  Natural killer (NK) cell repertoires are made up of phenotypically distinct subsets with different functional properties. The molecular programs involved in maintaining NK cell repertoire diversity under homeostatic conditions remain elusive. Here, we show that subset-specific NK cell proliferation kinetics correlate with mTOR activation, and global repertoire diversity is maintained through a high degree of intra-lineage subset plasticity during interleukin (IL)-15-driven homeostatic proliferation in vitro. Slowly cycling sorted KIR+CD56dim NK cells with an induced CD57 phenotype display increased functional potential associated with increased transcription of genes involved in adhesion and immune synapse formation. Rapidly cycling cells upregulate NKG2A, display a general loss of functionality, and a transcriptional signature associated with increased apoptosis/cellular stress, actin-remodeling, and nuclear factor κB (NF-κB) activation. These results shed light on the role of intra-lineage plasticity during NK cell homeostasis and suggest that the functional fate of the cell is tightly linked to the acquired phenotype and transcriptional reprogramming.

• Goodridge, Jodie; Jacobs, Benedikt Marcel; Sætersmoen, Michelle Lu; Clement, Dennis; Hammer, Quirin & Clancy, Trevor [Vis alle 24 forfattere av denne artikkelen] (2019). Remodeling of secretory lysosomes during education tunes functional potential in NK cells. Nature Communications. 10:14, s. 1–15. doi: 10.1038/s41467-019-08384-x. Fulltekst i vitenarkiv Vis sammendrag

  Inhibitory signaling during natural killer (NK) cell education translates into increased responsiveness to activation; however, the intracellular mechanism for functional tuning by inhibitory receptors remains unclear. Secretory lysosomes are part of the acidic lysosomal compartment that mediates intracellular signalling in several cell types. Here we show that educated NK cells expressing self-MHC specific inhibitory killer cell immunoglobulin-like receptors (KIR) accumulate granzyme B in dense-core secretory lysosomes that converge close to the centrosome. This discrete morphological phenotype is independent of transcriptional programs that regulate effector function, metabolism and lysosomal biogenesis. Meanwhile, interference of signaling from acidic Ca2+ stores in primary NK cells reduces target-specific Ca2+-flux, degranulation and cytokine production. Furthermore, inhibition of PI(3,5)P2 synthesis, or genetic silencing of the PI(3,5)P2-regulated lysosomal Ca2+-channel TRPML1, leads to increased granzyme B and enhanced functional potential, thereby mimicking the educated state. These results indicate an intrinsic role for lysosomal remodeling in NK cell education.

• Tutturen, Astrid Elisabeth Voorham; Dørum, Siri; Clancy, Trevor; Reims, Henrik Mikael; Christophersen, Asbjørn & Lundin, Knut Erik Aslaksen [Vis alle 9 forfattere av denne artikkelen] (2018). Characterization of the Small Intestinal Lesion in Celiac Disease by Label-Free Quantitative Mass Spectrometry. American Journal of Pathology. ISSN 0002-9440. 188(7), s. 1563–1579. doi: 10.1016/j.ajpath.2018.03.017. Fulltekst i vitenarkiv Vis sammendrag

  Global characterization of tissue proteomes from small amounts of biopsy material has become feasible because of advances in mass spectrometry and bioinformatics tools. In celiac disease (CD), dietary gluten induces an immune response that is accompanied by pronounced remodeling of the small intestine. Removal of gluten from the diet abrogates the immune response, and the tissue architecture normalizes. In this study, differences in global protein expression of small intestinal biopsy specimens from CD patients were quantified by analyzing formalin-fixed, paraffin-embedded material using liquid chromatography–mass spectrometry and label-free protein quantitation. Protein expression was compared in biopsy specimens collected from the same patients before and after 1-year treatment with gluten-free diet (n = 10) or before and after 3-day gluten provocation (n = 4). Differential expression of proteins in particular from mature enterocytes, neutrophils, and plasma cells could distinguish untreated from treated CD mucosa, and Ig variable region IGHV5-51 expression was found to serve as a CD-specific marker of ongoing immune activation. In patients who had undergone gluten challenge, coordinated up-regulation of wound response proteins, including the CD autoantigen transglutaminase 2, was observed. Our study provides a global and unbiased assessment of antigen-driven changes in protein expression in the celiac intestinal mucosa.

• Björklund, Andreas T.; Carlsten, Mattias; Sohlberg, Ebba; Liu, Lisa L.; Clancy, Trevor & Karimi, Mohsen [Vis alle 20 forfattere av denne artikkelen] (2018). Complete remission with reduction of high-risk clones following haploidentical NK-cell therapy against MDS and AML. Clinical Cancer Research. ISSN 1078-0432. 24(8), s. 1834–1844. doi: 10.1158/1078-0432.CCR-17-3196. Fulltekst i vitenarkiv
• Clancy, Trevor; dannenfelser, ruth; Troyanskaya, Olga G.; Malmberg, Karl-Johan; Hovig, Eivind & Kristensen, Vessela N. (2017). Bioinformatics approaches to profile the tumor microenvironment for immunotherapeutic discovery. Current pharmaceutical design. ISSN 1381-6128. 23(32), s. 4716–4725. doi: 10.2174/1381612823666170710154936. Fulltekst i vitenarkiv Vis sammendrag

  In the microenvironment of a malignancy, tumor cells do not exist in isolation, but rather in a diverse ecosystem consisting not only of heterogeneous tumor-cell clones, but also normal cell types such as fibroblasts, vasculature, and an extensive pool of immune cells at numerous possible stages of activation and differentiation. This results in a complex interplay of diverse cellular signaling systems, where the immune cell component is now established to influence cancer progression and therapeutic response. It is experimentally difficult and laborious to comprehensively and systematically profile these distinct cell types from heterogeneous tumor samples in order to capitalize on potential therapeutic and biomarker discoveries. One emerging solution to address this challenge is to computationally extract cell-type specific information directly from bulk tumors. Such in silico approaches are advantageous because they can capture both the cell-type specific profiles and the tissue systems level of cell-cell interactions. Accurately and comprehensively predicting these patterns in tumors is an important challenge to overcome, not least given the success of immunotherapeutic drug treatment of several human cancers. This is especially challenging for subsets of closely related immune cell phenotypes with relatively small gene expression differences, which have critical functional distinctions. Here, we outline the existing and emerging novel bioinformatics strategies that can be used to profile the tumor immune landscape.

• Clancy, Trevor & Hovig, Eivind (2016). Profiling networks of distinct immune-cells in tumors. BMC Bioinformatics. 17(1). doi: 10.1186/s12859-016-1141-3. Fulltekst i vitenarkiv Vis sammendrag

  Background It is now clearly evident that cancer outcome and response to therapy is guided by diverse immune-cell activity in tumors. Presently, a key challenge is to comprehensively identify networks of distinct immune-cell signatures present in complex tissue, at higher-resolution and at various stages of differentiation, activation or function. This is particularly so for closely related immune-cells with diminutive, yet critical, differences. Results To predict networks of infiltrated distinct immune-cell phenotypes at higher resolution, we explored an integrated knowledge-based approach to select immune-cell signature genes integrating not only expression enrichment across immune-cells, but also an automatic capture of relevant immune-cell signature genes from the literature. This knowledge-based approach was integrated with resources of immune-cell specific protein networks, to define signature genes of distinct immune-cell phenotypes. We demonstrate the utility of this approach by profiling signatures of distinct immune-cells, and networks of immune-cells, from metastatic melanoma patients who had undergone chemotherapy. The resultant bioinformatics strategy complements immunohistochemistry from these tumors, and predicts both tumor-killing and immunosuppressive networks of distinct immune-cells in responders and non-responders, respectively. The approach is also shown to capture differences in the immune-cell networks of BRAF versus NRAS mutated metastatic melanomas, and the dynamic changes in resistance to targeted kinase inhibitors in MAPK signalling. Conclusions This integrative bioinformatics approach demonstrates that capturing the protein network signatures and ratios of distinct immune-cell in the tumor microenvironment maybe an important factor in predicting response to therapy. This may serve as a computational strategy to define network signatures of distinct immune-cells to guide immuno-pathological discovery.

• Björklund, Andreas T.; Clancy, Trevor; Goodridge, Jodie; Béziat, Vivien; Schaffer, Marie & Hovig, Johannes Eivind [Vis alle 9 forfattere av denne artikkelen] (2016). Naive donor NK cell repertoires associated with less leukemia relapse after allogeneic hematopoietic stem cell transplantation. Journal of Immunology. ISSN 0022-1767. 196(3), s. 1400–1411. doi: 10.4049/jimmunol.1501434. Fulltekst i vitenarkiv
• Jonsson, Marte; Ragnum, Harald Bull; Halle, Cathinka Lønning; Yeramian, Andree; Clancy, Trevor & Frikstad, Kari-Anne [Vis alle 12 forfattere av denne artikkelen] (2016). Hypoxia-independent gene expression signature associated with radiosensitisation of prostate cancer cell lines by histone deacetylase inhibition. British Journal of Cancer. ISSN 0007-0920. 115(8), s. 929–939. doi: 10.1038/bjc.2016.278. Fulltekst i vitenarkiv
• Nygaard, Vigdis; Prasmickaite, Lina; Vasiliauskaite, Kotryna; Clancy, Trevor & Hovig, Johannes Eivind (2014). Melanoma brain colonization involves the emergence of a brain-adaptive phenotype. Oncoscience. 1(1), s. 82–94. doi: 10.18632/oncoscience.11. Fulltekst i vitenarkiv
• Nygård, Ståle; Reitan, Trond; Clancy, Trevor; Nygaard, Vegard; BJØRNSTAD, JOHANNES & Skrbic, Biljana [Vis alle 9 forfattere av denne artikkelen] (2014). Identifying pathogenic processes by integrating microarray data with prior knowledge. BMC Bioinformatics. 15(1). doi: 10.1186/1471-2105-15-115. Fulltekst i vitenarkiv Vis sammendrag

  Background It is of great importance to identify molecular processes and pathways that are involved in disease etiology. Although there has been an extensive use of various high-throughput methods for this task, pathogenic pathways are still not completely understood. Often the set of genes or proteins identified as altered in genome-wide screens show a poor overlap with canonical disease pathways. These findings are difficult to interpret, yet crucial in order to improve the understanding of the molecular processes underlying the disease progression. We present a novel method for identifying groups of connected molecules from a set of differentially expressed genes. These groups represent functional modules sharing common cellular function and involve signaling and regulatory events. Specifically, our method makes use of Bayesian statistics to identify groups of co-regulated genes based on the microarray data, where external information about molecular interactions and connections are used as priors in the group assignments. Markov chain Monte Carlo sampling is used to search for the most reliable grouping. Results Simulation results showed that the method improved the ability of identifying correct groups compared to traditional clustering, especially for small sample sizes. Applied to a microarray heart failure dataset the method found one large cluster with several genes important for the structure of the extracellular matrix and a smaller group with many genes involved in carbohydrate metabolism. The method was also applied to a microarray dataset on melanoma cancer patients with or without metastasis, where the main cluster was dominated by genes related to keratinocyte differentiation. Conclusion Our method found clusters overlapping with known pathogenic processes, but also pointed to new connections extending beyond the classical pathways.

• Clancy, Trevor & Hovig, Johannes Eivind (2014). Differential protein network analysis of the immune cell lineage. BioMed Research International. ISSN 2314-6133. 2014. doi: 10.1155/2014/363408. Fulltekst i vitenarkiv
• Clancy, Trevor & Hovig, Johannes Eivind (2014). From proteomes to complexomes in the era of systems biology. Proteomics. ISSN 1615-9853. 14(1), s. 24–41. doi: 10.1002/pmic.201300230. Fulltekst i vitenarkiv
• Bettum, Ingrid Johanne; Vasiliauskaite, Kotryna; Nygaard, Vigdis; Clancy, Trevor; Pettersen, Solveig & Tenstad, Ellen [Vis alle 8 forfattere av denne artikkelen] (2014). Metastasis-associated protein S100A4 induces a network of inflammatory cytokines that activate stromal cells to acquire pro-tumorigenic properties. Cancer Letters. ISSN 0304-3835. 344(1), s. 28–39. doi: 10.1016/j.canlet.2013.10.036. Fulltekst i vitenarkiv
• Sandve, Geir Kjetil; Gundersen, Sveinung; Johansen, Morten; Glad, Ingrid Kristine; Gunathasan, Krishanthi & Holden, Lars [Vis alle 21 forfattere av denne artikkelen] (2013). The Genomic HyperBrowser: an analysis web server for genome-scale data. Nucleic Acids Research (NAR). ISSN 0305-1048. 41(W1), s. W133–W141. doi: 10.1093/nar/gkt342. Fulltekst i vitenarkiv Vis sammendrag

  The immense increase in availability of genomic scale datasets, such as those provided by the ENCODE and Roadmap Epigenomics projects, presents unprecedented opportunities for individual researchers to pose novel falsifiable biological questions. With this opportunity, however, researchers are faced with the challenge of how to best analyze and interpret their genome-scale datasets. A powerful way of representing genome-scale data is as feature-specific coordinates relative to reference genome assemblies, i.e. as genomic tracks. The Genomic HyperBrowser (http://hyperbrowser.uio.no) is an open-ended web server for the analysis of genomic track data. Through the provision of several highly customizable components for processing and statistical analysis of genomic tracks, the HyperBrowser opens for a range of genomic investigations, related to, e.g., gene regulation, disease association or epigenetic modifications of the genome.

• Clancy, Trevor; Rødland, Einar Andreas; Nygård, Ståle & Hovig, Johannes Eivind (2013). Predicting Physical Interactions between Protein Complexes. Molecular & Cellular Proteomics. ISSN 1535-9476. 12(6), s. 1723–1734. doi: 10.1074/mcp.O112.019828. Fulltekst i vitenarkiv
• Lorvik, Kristina Berg; Haabeth, Ole Audun; Clancy, Trevor; Bogen, Bjarne & Corthay, Alexandre (2013). Molecular profiling of tumor-specific T(H)1 cells activated in vivo. Oncoimmunology. ISSN 2162-4011. 2(5:e24383). doi: 10.4161/onci.24383. Fulltekst i vitenarkiv
• Lando, Malin; Wilting, Saskia M.; Snipstad, Kristin; Clancy, Trevor; Bierkens, Mariska & Aarnes, Eva-Katrine [Vis alle 13 forfattere av denne artikkelen] (2013). Identification of eight candidate target genes of the recurrent 3p12p14 loss in cervical cancer by integrative genomic profiling. Journal of Pathology. ISSN 0022-3417. 230(1), s. 59–69. doi: 10.1002/path.4168. Fulltekst i vitenarkiv Vis sammendrag

  The pathogenetic role, including its target genes, of the recurrent 3p12–p14 loss in cervical cancer has remained unclear. To determine the onset of the event during carcinogenesis, we used microarray techniques and found that the loss was the most frequent 3p event, occurring in 61% of 92 invasive carcinomas, in only 2% of 43 high-grade intraepithelial lesions (CIN2/3), and in 33% of 6 CIN3 lesions adjacent to invasive carcinomas, suggesting a role in acquisition of invasiveness or early during the invasive phase. We performed an integrative DNA copy number and expression analysis of 77 invasive carcinomas, where all genes within the recurrent region were included. We selected eight genes, THOC7, PSMD6, SLC25A26, TMF1, RYBP, SHQ1, EBLN2, and GBE1, which were highly down-regulated in cases with loss, as confirmed at the protein level for RYBP and TMF1 by immunohistochemistry. The eight genes were subjected to network analysis based on the expression profiles, revealing interaction partners of proteins encoded by the genes that were coordinately regulated in tumours with loss. Several partners were shared among the eight genes, indicating crosstalk in their signalling. Gene ontology analysis showed enrichment of biological processes such as apoptosis, proliferation, and stress response in the network and suggested a relationship between down-regulation of the eight genes and activation of tumourigenic pathways. Survival analysis showed prognostic impact of the eight-gene signature that was confirmed in a validation cohort of 74 patients and was independent of clinical parameters. These results support the role of the eight candidate genes as targets of the 3p12–p14 loss in cervical cancer and suggest that the strong selection advantage of the loss during carcinogenesis might be caused by a synergetic effect of several tumourigenic processes controlled by these targets.

• Ågesen, Trude Holmeide; Berg, Marianne; Clancy, Trevor; Thiis-Evensen, Espen; Cekaite, Lina & Lind, Guro Elisabeth [Vis alle 16 forfattere av denne artikkelen] (2011). CLC and IFNAR1 are differentially expressed and a global immunity score is distinct between early- and late-onset colorectal cancer. Genes and Immunity. ISSN 1466-4879. 12(8), s. 653–662. doi: 10.1038/gene.2011.43. Fulltekst i vitenarkiv
• Halle, Cathinka Lønning; Lando, Malin; Svendsrud, Debbie Hege; Clancy, Trevor; Holden, Marit & Sundfør, Kolbein [Vis alle 9 forfattere av denne artikkelen] (2011). Membranous Expression of Ectodomain Isoforms of the Epidermal Growth Factor Receptor Predicts Outcome after Chemoradiotherapy of Lymph Node-Negative Cervical Cancer. Clinical Cancer Research. ISSN 1078-0432. 17(16), s. 5501–5512. doi: 10.1158/1078-0432.CCR-11-0297. Fulltekst i vitenarkiv
• Sandve, Geir Kjetil; Gundersen, Sveinung; Rydbeck, Halfdan; Glad, Ingrid Kristine; Holden, Lars & Holden, Marit [Vis alle 15 forfattere av denne artikkelen] (2011). The differential disease regulome. BMC Genomics. 12, s. 353–353. doi: 10.1186/1471-2164-12-353. Fulltekst i vitenarkiv Vis sammendrag

  Background Transcription factors in disease-relevant pathways represent potential drug targets, by impacting a distinct set of pathways that may be modulated through gene regulation. The influence of transcription factors is typically studied on a per disease basis, and no current resources provide a global overview of the relations between transcription factors and disease. Furthermore, existing pipelines for related large-scale analysis are tailored for particular sources of input data, and there is a need for generic methodology for integrating complementary sources of genomic information. Results We here present a large-scale analysis of multiple diseases versus multiple transcription factors, with a global map of over-and under-representation of 446 transcription factors in 1010 diseases. This map, referred to as the differential disease regulome, provides a first global statistical overview of the complex interrelationships between diseases, genes and controlling elements. The map is visualized using the Google map engine, due to its very large size, and provides a range of detailed information in a dynamic presentation format. The analysis is achieved through a novel methodology that performs a pairwise, genome-wide comparison on the cartesian product of two distinct sets of annotation tracks, e.g. all combinations of one disease and one TF. The methodology was also used to extend with maps using alternative data sets related to transcription and disease, as well as data sets related to Gene Ontology classification and histone modifications. We provide a web-based interface that allows users to generate other custom maps, which could be based on precisely specified subsets of transcription factors and diseases, or, in general, on any categorical genome annotation tracks as they are improved or become available. Conclusion We have created a first resource that provides a global overview of the complex relations between transcription factors and disease. As the accuracy of the disease regulome depends mainly on the quality of the input data, forthcoming ChIP-seq based binding data for many TFs will provide improved maps. We further believe our approach to genome analysis could allow an advance from the current typical situation of one-time integrative efforts to reproducible and upgradable integrative analysis. The differential disease regulome and its associated methodology is available at http://hyperbrowser.uio.no

• Clancy, Trevor; Pedicini, Marco; Castiglione, Filippo; Santoni, Daniele; Nygaard, Vegard & Lavelle, Timothy J. [Vis alle 8 forfattere av denne artikkelen] (2011). Immunological network signatures of cancer progression and survival. BMC Medical Genomics. 4. doi: 10.1186/1755-8794-4-28. Fulltekst i vitenarkiv Vis sammendrag

  Background The immune contribution to cancer progression is complex and difficult to characterize. For example in tumors, immune gene expression is detected from the combination of normal, tumor and immune cells in the tumor microenvironment. Profiling the immune component of tumors may facilitate the characterization of the poorly understood roles immunity plays in cancer progression. However, the current approaches to analyze the immune component of a tumor rely on incomplete identification of immune factors. Methods To facilitate a more comprehensive approach, we created a ranked immunological relevance score for all human genes, developed using a novel strategy that combines text mining and information theory. We used this score to assign an immunological grade to gene expression profiles, and thereby quantify the immunological component of tumors. This immunological relevance score was benchmarked against existing manually curated immune resources as well as high-throughput studies. To further characterize immunological relevance for genes, the relevance score was charted against both the human interactome and cancer information, forming an expanded interactome landscape of tumor immunity. We applied this approach to expression profiles in melanomas, thus identifying and grading their immunological components, followed by identification of their associated protein interactions. Results The power of this strategy was demonstrated by the observation of early activation of the adaptive immune response and the diversity of the immune component during melanoma progression. Furthermore, the genome-wide immunological relevance score classified melanoma patient groups, whose immunological grade correlated with clinical features, such as immune phenotypes and survival. Conclusions The assignment of a ranked immunological relevance score to all human genes extends the content of existing immune gene resources and enriches our understanding of immune involvement in complex biological networks. The application of this approach to tumor immunity represents an automated systems strategy that quantifies the immunological component in complex disease. In so doing, it stratifies patients according to their immune profiles, which may lead to effective computational prognostic and clinical guides.

• Beck, Halfdan; Nähse, Viola; Larsen, Marie Sofie Yoo; Groth, Petra; Clancy, Trevor & Lees, Michael [Vis alle 10 forfattere av denne artikkelen] (2010). Regulators of cyclin-dependent kinases are crucial for maintaining genome integrity in S phase. Journal of Cell Biology. ISSN 0021-9525. 188(5), s. 629–638. doi: 10.1083/jcb.200905059. Fulltekst i vitenarkiv
• Sandve, Geir Kjetil; Gundersen, Sveinung; Rydbeck, Halfdan; Glad, Ingrid Kristine; Holden, Lars & Holden, Marit [Vis alle 14 forfattere av denne artikkelen] (2010). The Genomic HyperBrowser: inferential genomics at the sequence level. Genome Biology. ISSN 1465-6906. 11(12). doi: 10.1186/gb-2010-11-12-r121. Fulltekst i vitenarkiv Vis sammendrag

  The immense increase in the generation of genomic scale data poses an unmet analytical challenge, due to a lack of established methodology with the required flexibility and power. We propose a first principled approach to statistical analysis of sequence-level genomic information. We provide a growing collection of generic biological investigations that query pairwise relations between tracks, represented as mathematical objects, along the genome. The Genomic HyperBrowser implements the approach and is available at http://hyperbrowser.uio.no.

• Pedicini, Marco; Barrenäs, Fredrik; Clancy, Trevor; Castiglione, Filippo; Hovig, Eivind & Kanduri, Kartiek [Vis alle 8 forfattere av denne artikkelen] (2010). Combining Network Modeling and Gene Expression Microarray Analysis to Explore the Dynamics of Th1 and Th2 Cell Regulation. PLoS Computational Biology. ISSN 1553-734X. 6(12). doi: 10.1371/journal.pcbi.1001032. Fulltekst i vitenarkiv

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• Federico, Lorenzo; Malone, Brandon; Tennøe, Simen; Chaban, Viktoriia; Osen, Julie Røkke & Gainullin, Murat [Vis alle 13 forfattere av denne artikkelen] (2024). Corrigendum: Experimental validation of immunogenic SARS-CoV-2 T cell epitopes identified by artificial intelligence (Frontiers in Immunology, (2023), 14, (1265044), 10.3389/fimmu.2023.1265044). Frontiers in Immunology. 15. doi: 10.3389/fimmu.2024.1377041. Fulltekst i vitenarkiv
• Nygård, Ståle; Reitan, Trond; Clancy, Trevor; Nygaard, Vegard; BJØRNSTAD, JOHANNES & Tønnessen, Theis [Vis alle 8 forfattere av denne artikkelen] (2011). Identifying pathogenic signaling and regulatory networks by integrating microarray data with prior knowledge. Fulltekst i vitenarkiv
• Nygård, Ståle; Reitan, Trond; Clancy, Trevor; Nygaard, Vegard; BJØRNSTAD, JOHANNES & Tønnessen, Theis [Vis alle 8 forfattere av denne artikkelen] (2011). Identifying pathogenic signaling and regulatory networks by integrating microarray data with prior knowledge. Fulltekst i vitenarkiv
• Nygård, Ståle; Nygaard, Vigdis; Clancy, Trevor; BJØRNSTAD, JOHANNES; Skrbic, Biljana & Sjaastad, Ivar [Vis alle 9 forfattere av denne artikkelen] (2010). Integrating microarray gene expression data with prior knowledge about molecular interactions for identification of important heart failure pathways. Fulltekst i vitenarkiv
• Nygård, Ståle; Nygaard, Vigdis; Clancy, Trevor; BJØRNSTAD, JOHANNES; Skrbic, Biljana & Tønnessen, Theis [Vis alle 8 forfattere av denne artikkelen] (2010). Integrating microarray gene expression data with prior knowledge about molecular interactions for identification of important heart failure pathways. Fulltekst i vitenarkiv
• Netskar, Herman Krogstad; Malmberg, Karl-Johan & Clancy, Trevor (2025). Single-Cell Mapping of Natural Killer Cell Diversity. Informing Strategies for Cancer Immunotherapy. Universitetet i Oslo. ISSN 9788234806414. Fulltekst i vitenarkiv Vis sammendrag

  Natural Killer (NK) cells play an important role in eliminating infected and transformed cells, including tumor cells. In recent years there has been an increased interest in using NK cells for cellular therapies against cancer. An increased understanding of the biology of NK cells and how different subsets and states of NK cells operate and respond to their environment can aid in efforts to improve NK cell-based therapies. The thesis provides a single-cell characterization of NK cells and established a transcriptional reference map of human NK cells. The reference map allowed for characterization of the perturbed states within tumor-infiltrating NK cells as these could be compared to the reference data. We identified six new states of NK cells, found across blood, tissues and tumors. Of particular interest, we identified a stressed state and a cytotoxic state, both of which were enriched across tumors. Analysis of overall survival of cancer patients showed these to be clinically relevant across different cancer types. The ratio of cytotoxic to stressed NK cells was positively associated with survival, highlighting the role NK cells can play as effectors against tumors. This might inform the design of NK cells for use in therapy. The thesis also provides an analysis of NK cells stimulated with IL-15 to capture the transcriptional profiles associated with NK subsets after stimulation. This data facilitated analysis of NK cells derived from induced pluripotent stem cells. These cells, known as iNK cells, is an important source of cells for the development of cellular therapies. The analysis provided in the thesis showed the iNK cells to exhibit an immature phenotype, but that they also display a cytotoxic profile. Genetically edited iNK cells were analyzed and compared to normal NK cells. This identified gaps in the transcriptional and regulatory repertoire of these cells which provides opportunities for further engineering to design better therapies in the future.

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