Dr Nicola Annels
Qualifications: BSc PhD
Phone: Work: 01483 68 8562
Room no: 09 PGM 02
9am to 5pm Monday-Friday
1992-1995 B.Sc. Upper Second Class (Hons), Biological Sciences, University of Southampton, UK
1995-1999 PhD., University of Birmingham, Immunology
Under the supervision of Prof. Alan Rickinson my research focused on CD8+ T cell responses to Epstein-Barr Virus (EBV) antigens.
1999-2000 Postdoctoral researcher, CRC Institute for Cancer Studies, University of Birmingham, Edgbaston, Birmingham, UK
The research followed on from my PhD using Epstein Barr virus as a model system in which to investigate the establishment of immunological memory
2000-2007 Postdoctoral Fellow, Leiden University Medical Center, Paediatrics, Leiden, The Netherlands
My project involved the identification of the homing receptor profiles and functional characterization of T cells involved in the pathogenesis and regulation of acute GvHD. In addition, I also collaborated with Prof. R.Maarten Egeler on a project trying to elucidate the pathophysiology and etiology of Langerhans cell histiocytosis.
2007-to date Senior Postdoctoral Fellow, Postgraduate Medical School, University of Surrey, Guildford, UK
I currently oversee the immunological research in the Oncology group headed by Prof Hardev Pandha. Our research projects focus on developing new immunotherapeutic strategies to treat cancer patients. This involves both the identification of novel immunotherapeutic target antigens as well as developing new strategies to abrogate the immunosuppressive mechanisms active in cancer.
Main interests are in tumour immunology, immunotherapy and regulatory T cells
- 'Oncolytic Immunotherapy for Bladder Cancer Using Coxsackie A21 Virus'.
Molecular Therapy - Oncolytics, 9, pp. 1-12.Repository URL: http://epubs.surrey.ac.uk/id/eprint/849859
As a clinical setting in which local live biological therapy is already well established, non-muscle invasive bladder cancer (NMIBC) presents intriguing opportunities for oncolytic virotherapy. Coxsackievirus A21 (CVA21) is a novel intercellular adhesion molecule-1 (ICAM-1)-targeted immunotherapeutic virus. This study investigated CVA21-induced cytotoxicity in a panel of human bladder cancer cell lines, revealing a range of sensitivities largely correlating with expression of the viral receptor ICAM-1. CVA21 in combination with low doses of mitomycin-C enhanced CVA21 viral replication and oncolysis by increasing surface expression levels of ICAM-1. This was further confirmed using 300-μm precision slices of NMIBC where levels of virus protein expression and induction of apoptosis were enhanced with prior exposure to mitomycin-C. Given the importance of the immunogenicity of dying cancer cells for triggering tumor-specific responses and long-term therapeutic success, the ability of CVA21 to induce immunogenic cell death was investigated. CVA21 induced immunogenic apoptosis in bladder cancer cell lines, as evidenced by expression of the immunogenic cell death (ICD) determinant calreticulin, and HMGB-1 release and the ability to reject MB49 tumors in syngeneic mice after vaccination with MB49 cells undergoing CVA21 induced ICD. Such CVA21 immunotherapy could offer a potentially less toxic, more effective option for the treatment of bladder cancer.
- 'Immunohistochemistry Biomarkers in Nonmuscle Invasive Bladder Cancer.'.
Applied immunohistochemistry & molecular morphology : AIMM / official publication of the Society for Applied Immunohistochemistry,
Bladder cancer (BCa) is the most frequent urinary tract neoplasm. BCa results in significant mortality when the disease presents as muscle invasive. Around 75% to 80% of patients present with nonmuscle invasive bladder cancer (NMIBC), but recurrence and progression are significant issues, compelling current guidelines to recommend long-term surveillance. There is therefore an urgent and unmet need to identify and validate accurate biomarkers for the detection of disease recurrence to improve quality of life for the patients and reduce costs for health care providers, while maintaining or improving current outcomes. In this review, 38 publications on immunohistochemistry prognostic biomarkers, that were studied may be related in nonmuscle invasive bladder cancer, have been analyzed. The studies were organized according to the evaluated marker and their findings. It was demonstrated that the combination of independent complementary biomarkers could allow a more accurate prognosis than an isolated marker. Biomarkers, including p53, Ki-67, and CK20, with classic and prognostic factors with recurrence and novel markers such as EN2 may provide a more accurate prediction of outcome compared with any single marker, improving risk stratification and clinical management of patients with BCa.
- 'Spontaneous antibodies against Engrailed-2 (EN2) protein in patients with prostate cancer.'.
Clin Exp Immunol, England: 177 (2), pp. 428-438.doi: 10.1111/cei.12332Repository URL: http://epubs.surrey.ac.uk/806599/
We reported the expression of the homeodomain-containing transcription factor Engrailed-2 (EN2) in prostate cancer and showed that the presence of EN2 protein in the urine was highly predictive of prostate cancer. This study aimed to determine whether patients with prostate cancer have EN2 autoantibodies, what the prevalence of these antibodies is and whether they are associated with disease stage. The spontaneous immunoglobulin (Ig)G immune response against EN2 and for comparison the tumour antigen New York Esophageal Squamous Cell Carcinoma 1 (NY-ESO-1), were tested by enzyme-linked immunosorbent assay (ELISA) in three different cohorts of prostate cancer patients as well as a group of men genetically predisposed to prostate cancer. Thirty-two of 353 (9·1%) of the SUN cohort representing all stages of prostate cancer demonstrated EN2 IgG responses, 12 of 107 patients (11·2%) in the advanced prostate cancer patients showed responses, while only four of 121 patients (3·3%) with castrate-resistant prostate cancer showed EN2 autoantibodies. No significant responses were found in the predisposed group. Anti-EN2 IgG responses were significantly higher in patients with prostate cancer compared to healthy control males and similarly prevalent to anti-NY-ESO-1 responses. While EN2 autoantibodies are not a useful diagnostic or monitoring tool, EN2 immunogenicity provides the rationale to pursue studies using EN2 as an immunotherapeutic target.
- 'Prostate cancer vaccines.'.
Expert Review of Vaccines, 12 (3), pp. 253-262.doi: 10.1586/erv.13.27Repository URL: http://epubs.surrey.ac.uk/id/eprint/769594
In 2010, the US FDA approved the first therapeutic cancer vaccine for the treatment of castration refractory prostate cancer - sipuleucel-T. Prostate cancer is an ideal model for cancer vaccine development based on the ready demonstration of humoral and cellular immunity to a range of cancer antigens as well as often slow progression which means that patients who are otherwise well may have a radiologically evaluable minor progression, after conventional treatment and can undergo vaccine therapy over sufficient periods of time, so as to allow the generation of a robust antitumor response. The association of prostate cancer with one of the few serum cancer biomarkers in general use has also allowed assessment of response and risk stratification of patients. In this review, we will examine key aspects of the evolution of prostate cancer vaccines, which provides an accurate prototype for other cancers, and the challenges we face.
- 'The effects of gemcitabine and capecitabine combination chemotherapy and of low-dose adjuvant GM-CSF on the levels of myeloid-derived suppressor cells in patients with advanced pancreatic cancer.'.
Cancer Immunol Immunother, Repository URL: http://epubs.surrey.ac.uk/806602/
In pre-clinical models, the only two chemotherapy drugs which have been demonstrated to directly reduce the number of myeloid-derived suppressor cells (MDSCs) are gemcitabine and 5-fluorouracil. Here we analyze the dynamics of MDSCs, phenotyped as Lin-DR-CD11b+, in patients with advanced pancreatic cancer receiving the combination of gemcitabine and capecitabine, a 5-FU pro-drug. We found no evidence that gemcitabine and capecitabine directly reduce MDSC% in patients. Gemcitabine and capecitabine reduced MDSCs in 42 % of patients (n = 19) and MDSC% fell in only 3/9 patients with above-median baseline MDSCs. In 5/8 patients with minimal tumour volume change on treatment, the MDSC% went up: increases in MDSC% in these patients appeared to correlate with sustained cancer-related inflammatory cytokine upregulation. In a separate cohort of 21 patients treated with gemcitabine and capecitabine together with concurrently administered GV1001 vaccine with adjuvant GM-CSF, the MDSC% fell in 18/21 patients and there was a significant difference in the trajectory of MDSCs between those receiving GV1001 and GM-CSF in combination with chemotherapy and those receiving chemotherapy alone. Thus, there was no evidence that the addition of low-dose adjuvant GM-CSF increased Lin-DR-CD11b+ MDSC in patients receiving combination chemoimmunotherapy. 9/21 patients developed an immune response to GV1001 and the MDSCs fell in 8 of these 9 patients, 6 of whom had above-median pre-vaccination MDSC levels. A high pre-vaccination MDSC% does not preclude the development of immunity to a tumour-associated antigen.
- 'Combination of a fusogenic glycoprotein, pro-drug activation and oncolytic HSV as an intravesical therapy for superficial bladder cancer'.
BRITISH JOURNAL OF CANCER, 106 (3), pp. 496-507.doi: 10.1038/bjc.2011.577
- 'Are we ready to start studies of Th17 cell manipulation as a therapy for cancer?'.
Cancer Immunol Immunother, Germany: 61 (1), pp. 1-7.
From a therapeutic perspective, the bourgeoning literature on Th17 cells should allow us to decide whether to rationally pursue the manipulation of Th17 cells in cancer. The purpose of this review is to attempt a synthesis of a number of contradictory conclusions as to the role that these cells are playing in the process of tumourigenesis in order to provide guidance as to whether our current understanding is sufficient to safely pursue Th17-targeted therapy in cancer at this time. Th17 cells are a highly plastic population and the cytokine drivers for Th17 cell generation and skewing will vary between various cancers and importantly between different sites of tumour involvement in any individual patient. The net impact of the pro-angiogenic IL-17 produced not only by Th17 cells but by other cells particularly macrophages and the anti-tumour effects of Th1/Th17 cells will in turn be determined by the complex interplay of diverse chemokines and cytokines in any tumour microenvironment. Th17 cells that fail to home to tumours may be immunosuppressive. The complexity of IL-17 and Th17 dynamics makes easy prediction of the effects of either enhancing or suppressing Th17 cell differentiation in cancer problematic.
- 'Elevated myeloid-derived suppressor cells in pancreatic, esophageal and gastric cancer are an independent prognostic factor and are associated with significant elevation of the Th2 cytokine interleukin-13.'.
Cancer Immunol Immunother,
We undertook a comprehensive analysis of circulating myeloid-derived suppressor cells (MDSCs) and T regulatory cells (Tregs) in pancreatic, esophageal and gastric cancer patients and investigated whether MDSCs are an independent prognostic factor for survival. We evaluated a series of plasma cytokines and in particular re-evaluated the Th2 cytokine interleukin-13 (IL-13). Peripheral blood was collected from 131 cancer patients (46 pancreatic, 60 esophageal and 25 gastric) and 54 healthy controls. PBMC were harvested with subsequent flow cytometric analysis of MDSC (HLADR(-) Lin1(low/-) CD33(+) CD11b(+)) and Treg (CD4(+) CD25(+) CD127(low/-) FoxP3(+)) percentages. Plasma IL-2, IL-4, IL-5, IL-6, IL-10, IL-12 (p70), IL-13, IL-17, G-CSF, IFN-γ, TNF-α and VEGF levels were analyzed by the Bio-Plex cytokine assay. Plasma arginase I levels were analyzed by ELISA. MDSCs and Tregs were statistically significantly elevated in pancreatic, esophageal and gastric cancer compared with controls, and MDSC numbers correlated with Treg levels. Increasing MDSC percentage was associated with increased risk of death, and in a multivariate analysis, MDSC level was an independent prognostic factor for survival. A unit increase in MDSC percentage was associated with a 22% increased risk of death (hazard ratio 1.22, 95% confidence interval 1.06-1.41). Arginase I levels were also statistically significantly elevated in upper gastrointestinal cancer patients compared with controls. There was Th2 skewing for cytokine production in all three diseases, and importantly there were significant elevations of the pivotal Th2 cytokine interleukin-13, an increase that correlated with MDSC levels.
- 'Use of gemcitabine- (Gem) and fluropyrimidine (FP)-based chemotherapy to reduce myeloid-derived suppressor cells (MDSCs) in pancreatic (PC) and esophagogastric cancer (EGC).'. JOURNAL OF CLINICAL ONCOLOGY, 29 (15) . (2011)
- 'EN2: A candidate antigen for the development of targeted therapies in ovarian cancer.'.
JOURNAL OF CLINICAL ONCOLOGY, 29 (15)Repository URL: http://epubs.surrey.ac.uk/id/eprint/826910
- 'Engrailed-2 (EN2): a tumor specific urinary biomarker for the early diagnosis of prostate cancer.'.
Clin Cancer Res, United States: 17 (5), pp. 1090-1098.Repository URL: http://epubs.surrey.ac.uk/2751/
PURPOSE: Prostate cancer (PC) is the second most common cause of cancer related death in men. A number of key limitations with prostate specific antigen (PSA), currently the standard detection test, has justified evaluation of new biomarkers. We have assessed the diagnostic potential of Engrailed-2 (EN2) protein, a homeodomain-containing transcription factor expressed in PC cell lines and secreted into the urine by PC in men. EXPERIMENTAL DESIGN: EN2 expression in PC cell lines and prostate cancer tissue was determined by semi-quantative RT-PCR and immunohistochemistry. First pass urine [without prior digital rectal examination (DRE)] was collected from men presenting with urinary symptoms (referred to exclude/confirm the presence of prostate cancer) and from controls. EN2 protein was measured by ELISA in urine from men with PC (n = 82) and controls (n = 102). RESULTS: EN2 was expressed and secreted by PC cell lines and PC tissue but not by normal prostate tissue or stroma. The presence of EN2 in urine was highly predictive of PC, with a sensitivity of 66% and a specificity of 88.2%, without requirement for DRE. There was no correlation with PSA levels. These results were confirmed independently by a second academic center. CONCLUSIONS: Urinary EN2 is a highly specific and sensitive candidate biomarker of prostate cancer. A larger multicenter study to further evaluate the diagnostic potential of EN2 is justified.
- 'Elevated myeloid-derived suppressor cells in pancreatic, esophageal and gastric cancer are an independent prognostic factor and are associated with significant elevation of the Th2 cytokine interleukin-13'.
Cancer Immunology, Immunotherapy, 60 (10), pp. 1419-1430.
We undertook a comprehensive analysis of circulating myeloid-derived suppressor cells (MDSCs) and T regulatory cells (Tregs) in pancreatic, esophageal and gastric cancer patients and investigated whether MDSCs are an independent prognostic factor for survival. We evaluated a series of plasma cytokines and in particular re-evaluated the Th2 cytokine interleukin-13 (IL-13). Peripheral blood was collected from 131 cancer patients (46 pancreatic, 60 esophageal and 25 gastric) and 54 healthy controls. PBMC were harvested with subsequent flow cytometric analysis of MDSC (HLADR - Lin1 low/- CD33 + CD11b +) and Treg (CD4 + CD25 + CD127 low/- FoxP3 +) percentages. Plasma IL-2, IL-4, IL-5, IL-6, IL-10, IL-12 (p70), IL-13, IL-17, G-CSF, IFN-γ, TNF-α and VEGF levels were analyzed by the Bio-Plex cytokine assay. Plasma arginase I levels were analyzed by ELISA. MDSCs and Tregs were statistically significantly elevated in pancreatic, esophageal and gastric cancer compared with controls, and MDSC numbers correlated with Treg levels. Increasing MDSC percentage was associated with increased risk of death, and in a multivariate analysis, MDSC level was an independent prognostic factor for survival. A unit increase in MDSC percentage was associated with a 22% increased risk of death (hazard ratio 1.22, 95% confidence interval 1.06-1.41). Arginase I levels were also statistically significantly elevated in upper gastrointestinal cancer patients compared with controls. There was Th2 skewing for cytokine production in all three diseases, and importantly there were significant elevations of the pivotal Th2 cytokine interleukin-13, an increase that correlated with MDSC levels. © 2011 The Author(s).
- 'The Effect of Cell Cycle Synchronization on Tumor Sensitivity to Reovirus Oncolysis'.
MOLECULAR THERAPY, 18 (12), pp. 2085-2093.doi: 10.1038/mt.2010.189
- 'Chemokine/Chemokine Receptor Interactions in Extramedullary Leukaemia of the Skin in Childhood AML: Differential Roles for CCR2, CCR5, CXCR4 and CXCR7'.
PEDIATRIC BLOOD & CANCER, 55 (2), pp. 344-348.doi: 10.1002/pbc.22500
- 'Decrease of Skin Infiltrating and Circulating CCR10+T Cells Coincides with Clinical Improvement after Topical Tacrolimus in Omenn Syndrome'.
JOURNAL OF INVESTIGATIVE DERMATOLOGY, 130 (1), pp. 308-311.doi: 10.1038/jid.2009.196
- 'LANGERHANS CELL HISTIOCYTOSIS REVEALS A NEW IL-17A-DEPENDENT PATHWAY OF DENDRITIC CELL FUSION'.
PEDIATR BLOOD CANCER, 53 (4), pp. 686-686.doi: 10.1038/nm1694
- 'No Genomic Aberrations in Langerhans Cell Histiocytosis as Assessed by Diverse Molecular Technologies'.
GENES CHROMOSOMES & CANCER, 48 (3), pp. 239-249.doi: 10.1002/gcc.20634
- 'Langerhans cell histiocytosis reveals a new IL-17A dependent pathway of dendritic cell fusion'.
NATURE MEDICINE, 14 (1), pp. 81-87.doi: 10.1038/nm1694
- 'Investigation of potential chromosomal abnormalities in the lesional cells of Langerhans cell histiocytosis'. PEDIATRIC BLOOD & CANCER, 48 (7), pp. 753-754. . (2007)
- 'Differences in telomerase expression by the CD1a(+) cells in Langerhans cell histiocytosis reflect the diverse clinical presentation of the disease'.
JOURNAL OF PATHOLOGY, 212 (2), pp. 188-197.doi: 10.1002/path.2167
- 'Management of Epstein-Barr virus (EBV) reactivation after allogeneic stem cell transplantation by simultaneous analysis of EBV DNA load and EBV-specific T cell reconstitution'.
CLINICAL INFECTIOUS DISEASES, 42 (12), pp. 1743-1748.doi: 10.1086/503838
- 'A possible role for CCL27/CTACK-CCR10 interaction in recruiting CD4(+) T cells to skin in human graft-versus-host disease'. BRITISH JOURNAL OF HAEMATOLOGY, 133 (5), pp. 538-549. . (2006)
- 'Presence of osteoclast-like multinucleated giant cells in the bone and nonostotic lesions of Langerhans cell histiocytosis'.
JOURNAL OF EXPERIMENTAL MEDICINE, 201 (5), pp. 687-693.doi: 10.1084/jem.20041785
- 'The role of multinucleated giant cells in Langerhans cell histiocytosis'. PEDIATRIC BLOOD & CANCER, 43 (2), pp. 199-199. . (2004)
- 'Commentary - Langerhans cell histiocytosis: A pathologic combination of oncogenesis and immune dysregulation'.
PEDIATRIC BLOOD & CANCER, 42 (5), pp. 401-403.doi: 10.1002/pbc.10464
- 'Possible link between unique chemokine and homing receptor expression at diagnosis and relapse location in a patient with childhood T-ALL'. BLOOD, 103 (7), pp. 2806-2808. . (2004)
- 'Response to Fadeel and Henter: Langerhans cell histiocytosis: a combination of carcinogenesis and inflammation'. TRENDS IN IMMUNOLOGY, 24 (8), pp. 410-411. . (2003)
- 'Aberrant chemokine receptor expression and chemokine production by Langerhans cells underlies the pathogenesis of Langerhans cell histiocytosis'.
JOURNAL OF EXPERIMENTAL MEDICINE, 197 (10), pp. 1385-1390.doi: 10.1084/jem.20030137
- 'Langerhans-cell histiocytosis 'insight into DC biology''. TRENDS IN IMMUNOLOGY, 24 (4), pp. 190-196. . (2003)
- 'Epstein-Barr virus-specific CD8(+) T cells that re-express CD45RA are apoptosis-resistant memory cells that retain replicative potential'. BLOOD, 100 (3), pp. 933-940. . (2002)
- 'Epitope-specific evolution of human CD8(+) T cell responses from primary to persistent phases of Epstein-Barr virus infection'.
JOURNAL OF EXPERIMENTAL MEDICINE, 195 (7), pp. 893-905.doi: 10.1084/jem.20011692
- 'Memory T cells constitute a subset of the human CD8(+)CD45RA(+) pool with distinct phenotypic and migratory characteristics'. JOURNAL OF IMMUNOLOGY, 167 (1), pp. 212-220. . (2001)
- 'Changing patterns of dominant TCR usage with maturation of an EBV-specific cytotoxic T cell response'. JOURNAL OF IMMUNOLOGY, 165 (9), pp. 4831-4841. . (2000)
- 'A re-evaluation of the frequency of CD8(+) T cells specific for EBV in healthy virus carriers'. JOURNAL OF IMMUNOLOGY, 162 (3), pp. 1827-1835. . (1999)
- 'Immediate early and early lytic cycle proteins are frequent targets of the Epstein-Barr virus-induced cytotoxic T cell response'. JOURNAL OF EXPERIMENTAL MEDICINE, 185 (9), pp. 1605-1617. . (1997)
- 'Epitope focusing in the primary cytotoxic T cell response to Epstein-Barr virus and its relationship to T cell memory'. JOURNAL OF EXPERIMENTAL MEDICINE, 184 (5), pp. 1801-1813. . (1996)
- 'Engrailed 2 protein (EN2) as a novel biomarker in epithelial ovarian cancer'. ELSEVIER SCI LTD EUROPEAN JOURNAL OF CANCER, Vienna, AUSTRIA: European Cancer Congress 51, pp. S91-S91. . (2015)
- 'Resistance to Oncolytic Reovirus is associated with high expression of Yes-Associated Protein-1 (YAP-1) in Head and Neck Cancer'. MARY ANN LIEBERT, INC HUMAN GENE THERAPY, Lincoln Coll & Examinat Sch, Oxford, ENGLAND: 8th International Conference on Oncolytic Virus Therapeutics 25 (12), pp. A12-A13. . (2014)
- 'Major synergy between Coxsackievirus A21 (CAVATAK (TM)) and radiotherapy or chemotherapy in bladder cancer'. ELSEVIER SCI LTD
EUROPEAN JOURNAL OF CANCER, European Org Res & Treatment Canc, Barcelona, SPAIN: 26th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics 50, pp. 41-42.Repository URL: http://epubs.surrey.ac.uk/id/eprint/827970
- 'Engrailed-2 (EN2) protein expression and prognosis in bladder cancer following radical cystectomy (RC).'. AMER SOC CLINICAL ONCOLOGY JOURNAL OF CLINICAL ONCOLOGY, Chicago, IL: 50th Annual Meeting of the American-Society-of-Clinical-Oncology 32 (15) . (2014)
- 'Modulation of Regulatory T Cells by Targeting The NFAT-FOXP3 Protein: Protein Interaction'. LIPPINCOTT WILLIAMS & WILKINS JOURNAL OF IMMUNOTHERAPY, North Bethesda, MD: 27th Annual Scientific Meeting of the Society-for-Immunotherapy-of-Cancer (SITC) 35 (9), pp. 775-775. . (2012)
- 'Engrailed protein: A cancer-specific marker in epithelial ovarian cancer'. AMER SOC CLINICAL ONCOLOGY JOURNAL OF CLINICAL ONCOLOGY, Chicago, IL: 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) 30 (15) . (2012)
- 'Detecting prostate cancer in BRCA1 and BRCA2 mutation carriers: A role for EN2?'. AMER SOC CLINICAL ONCOLOGY JOURNAL OF CLINICAL ONCOLOGY, Chicago, IL: 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) 30 (15) . (2012)
- 'EN2: A candidate antigen for the development of targeted therapies in ovarian cancer.'.
JCO, Chicago: ASCO (J Clin)Repository URL: http://epubs.surrey.ac.uk/id/eprint/824541
Background: Ovarian cancer remains the most lethal gynaecologic tumour in the Western world. Stimulation of the immune system to consolidate response to chemotherapy can potentially be beneficial however so far none of the vaccination strategies have offered survival advantage. Thus identifying and targeting clinically relevant antigens for immunotherapy continues to be an important research strategy. We have evaluated Engrailed-2 (EN2) as a potential target for vaccine strategy. EN2 is a homeodomain-containing transcription factor with a multifunctional role in neural development. There is evidence that over-expression of EN2 protein maybe linked to tumour development. Methods: Ovarian cancer cell lines were analysed by FACS for EN2 cell surface expression. EN2 expression in ovarian cancer tissue arrays were done by immunohistochemistry. A serum analysis (ELISA) was done to evaluate the presence of antibodies to EN2 in ovarian cancer patients and age-matched controls. A set of potentially immunogenic HLA-A2 restricted epitopes from the EN2 protein was identified using a computer algorithm SYFPEITHI. These peptides have been tested on HLA-A2 positive ovarian cancer patients’ PBMC using an in vitro culture method. The specificity of these T cell lines was analysed against T2 target cells loaded with or without EN2 peptides Results: Cell surface expression of EN2 was observed in ovarian cancer cell lines OVCAR3, OV90, CaOV-3, ES-2 and SKOV-3 of which ES-2 and SKOV3 showed strong expression. EN2 was also present in approximately 80% of ovarian cancer tissues whereas EN-2 expression was very low (<10%) or absent in normal tissues. Out of the 67 ovarian cancer patients 20.9% (14/67) had antibodies against EN2 compared to 2.4% (1/42) of age-matched female controls. 4 of the identified EN2 epitopes were able to generate peptide specific cytotoxic T lymphocytes in the ovarian cancer patients tested. Conclusions: The over-expression and immunogenicity of EN2 in ovarian cancer makes it a credible antigen to exploit as a novel target for ovarian cancer immunotherapy. ž
- 'Predominance of CD8 T cell infiltration coincides with reciprocal reduction in regulatory T cells following prostate cryotherapy'. WILEY-BLACKWELL BRITISH JOURNAL OF SURGERY, Royal Coll Surgery, Dublin, IRELAND: Annual Meeting of the Society-of-Academic-and-Research-Surgery 98, pp. 48-48. . (2011)
- 'Combination of a fusogenic glycoprotein, pro-drug activation and oncolytic HSV as an intravesical therapy for superficial bladder cancer'. PERGAMON-ELSEVIER SCIENCE LTD EJC SUPPLEMENTS, Geneva, SWITZERLAND: 20th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics 6 (12), pp. 97-98. . (2008)
- 'Differences in telomerase expression by the CD1 a+ cells in langerhans cell histiocytosis reflects the diverse clinical presentation of the disease'. ACADEMIC PRESS INC ELSEVIER SCIENCE CLINICAL IMMUNOLOGY, San Diego, CA: 7th Annual Meeting of the Federation-of-Clinical-Immunology-Societies 123, pp. S50-S50. . (2007)
- 'Identification of a clonal population of CCR10+ skin-homing T-cells in an Omenn Syndrome patient.'. ACADEMIC PRESS INC ELSEVIER SCIENCE CLINICAL IMMUNOLOGY, San Francisco, CA: 6th Annual Meeting of the Federation-of-Clinical-Immunology-Societies 119, pp. S128-S129. . (2006)
- 'Possible involvement of CCL28 in the localisation of CCR3+T-cells in intestinal GvHD'. NATURE PUBLISHING GROUP BONE MARROW TRANSPLANTATION, Prague, CZECH REPUBLIC: 31st Annual Meeting of the European-Group-for-Blood-and-Marrow-Transplantation/21st Meeting of the EBMT-Nurses-Group/4th Meeting of the EBMT-Data-Management-Group 35, pp. S134-S134. . (2005)
- 'Identification Of a skin-homing population of CD4+T cells in patients with skin GvHD'. NATURE PUBLISHING GROUP BONE MARROW TRANSPLANTATION, Prague, CZECH REPUBLIC: 31st Annual Meeting of the European-Group-for-Blood-and-Marrow-Transplantation/21st Meeting of the EBMT-Nurses-Group/4th Meeting of the EBMT-Data-Management-Group 35, pp. S134-S135. . (2005)
- 'T-cell memory: lessons from Epstein-Barr virus infection in man'. ROYAL SOC LONDON PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY OF LONDON SERIES B-BIOLOGICAL SCIENCES, LONDON, ENGLAND: Synposium on Immunological Memory 355 (1395), pp. 391-400. . (2000)
- 'Immunotherapy'. in (ed.) Prostate Cancer: A Comprehensive Perspective
, pp. 925-934.
© 2013 Springer-Verlag London. All rights are reserved.The approval in April 2010 by the FDA in the USA of a prostate cancer vaccine (Sipuleucel-T, Provenge, Dendreon Inc.) may herald a new era in T-cell-directed cancer therapies. The magnitude of scientific effort to reach this point should not be underestimated. The key has been unraveling the complex mechanisms between the recognition of tumor antigen, breaking immune tolerance, and generation of a long-lasting and clinically meaningful cellular response. Therapeutic vaccines (i.e., vaccines for patients with ongoing disease) have two objectives: priming Ag-specific T cells and reprogramming memory T cells (i.e., a transformation from one type of immunity to another, for example, regulatory to cytotoxic). Numerous therapeutic approaches have been tested in prostate cancer patients, including autologous and allogeneic tumor cells modified to express various cytokines, peptides, proteins, and DNA vaccines. The evolution of cellular vaccines includes addressing the local immunosuppressive tumor microenvironment, modulating immune response through checkpoint blockade and, importantly, combining cellular immunotherapy with other treatment modalities such as chemotherapy exploiting their intrinsic immunomodulatory properties.
Theses and dissertations
- Engrailed-2(EN2) expression in ovarian cancer..
[ Status: Approved ]Repository URL: http://epubs.surrey.ac.uk/id/eprint/807874
Epithelial ovarian cancer (EOC) is a common malignancy, usually diagnosed at an advanced stage, resulting in over 4,000 deaths each year in the UK. There is currently no National Screening Programme and no clinically approved diagnostic biomarker. Engrailed-2 (EN2) is a homeodomain-containing transcription factor, essential during embryological neural development, which is dysregulated in several cancer types. We have studied the biology and function of EN2, and have investigated the potential role as a biomarker in EOC tissue and bodily fluids. Elevated En2 mRNA expression levels and protein staining were observed in EOC tissue, but levels were much lower in benign tumours, and negligible in normal ovary. Therefore EN2 could be utilised as a diagnostic biomarker, particularly in high-grade serous tumours (HGSOC), however this would require an invasive biopsy specimen. Urine samples are more easily obtainable and EN2 protein was positive in 86% of newly diagnosed HGSOC, compared with female healthy controls, making it a potential non-invasive diagnostic biomarker and possible screening tool. In HGSOC patients who received neoadjuvant chemotherapy prior to surgery, elevated En2 mRNA levels and positive protein expression predicted a shorter progression-free survival and resistance to platinum chemotherapy. Such information could be used as a prognostic biomarker to guide post-operative treatment decisions. In normal adult Purkinje neurons EN2 is located in the nucleus at 33kDa, however EN2 was cytoplasmic and visualised at 43kDa or 50kDa in EOC, suggesting post-translational modification from the native state. En2 over-expression studies, including microarray analysis and cisplatin-challenge, suggested a role in the development of platinum-resistance. EN2 was also implicated in cell invasion and metastasis, via the process of epithelial-mesenchymal transition (EMT). EN2 appears to be actively involved in disease progression and treatment resistance in EOC, and further research determining its role in EMT, and the TGFβ receptor and Wnt signalling pathways is warranted. It also shows potential as a clinical biomarker, especially in urine where the non-invasive nature of the test and the potential for detection prior to any clinical signs or symptoms, make it a worthy candidate for ongoing research.