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Dr Stephen Man

Dr Stephen Man

Reader

School of Medicine

Email:
mans@cardiff.ac.uk
Telephone:
+44 29206 87056
Location:
Cancer Genetics Building, University Hospital of Wales, Heath Park, Cardiff, CF14 4XN

I am a Reader in the Division of Cancer and Genetics (DCG), in the School of Medicine. My research is focussed on the role of the immune system in cancer. I am an expert on human T cells and for the last five years, I have been studying the role of these cells in leukaemia. My research funded by Bloodwise and Cancer Research Wales has identified novel targets for immune attack, and shown that patients with more aggressive disease have abnormal T cell populations. Our aim is to translate these findings for patient benefit.

Career Overview

  • 2013-present: Reader, Division of Cancer and Genetics, School of Medicine, Cardiff University
  • 2002-2012: Senior Lecturer, Infection and Immunity, School of Medicine, Cardiff University
  • 1995-2003: Royal Society University Research Fellow, Department of Medicine, University of Wales College of Medicine
  • 1994-1995: Post-doctoral Research Fellow, Department of Medicine, University of Wales College of Medicine
  • 1990-1994: Post-doctoral Research Fellow, Department of Microbiology, University of Virginia, USA

Professional memberships

  • Member of the British Society for Immunology

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  • Man, S. T.et al. 1999. Recombinant vaccinia virus. In: Tindle, R. W. ed. Vaccines for Human Papillomavirus Infection and anogenital disease, 14th ed... Medical Intelligence Unit Austin, Texas: R.G. Landes Company, pp. 69-90.

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I lecture and perform course assessment for the Advanced Immunology (ME3045) and Immunopathology and Immunotherapy (ME3046) Modules.

I am an academic mentor to 10 medical students (1st and 4th years).

I supervise SSC projects for medical students, which include laboratory projects for year 2 students and tutor lead/bespoke projects for years 3 and 4. In the last two years I have supervised 13 medical students on a community engagement project (Interactive Health Workshops for Welsh Primary Schools). More details can be found under the Engagement tab.

I am also a supervisor to 3 full-time PhD students.

My research is focussed on the role of the immune system in cancer, in particular trying to develop new ways to treat cancer or to monitor the status of the immune system to identify poor prognosis patients.  Over the last 5 years I have been working in a team dedicated to the study of Chronic Lymphocytic Leukaemia (CLL). My laboratory has three main research topics:

Tumour Specific Targets

For effective cancer therapy, T cells must be specifically targeted to cancer cells but not cause harm to normal healthy tissue. Ideally T cell targets should be applicable to a broad range of human cancers.

We demonstrated proof of concept for a novel type of tumour antigen, based on the intrinsic biological properties of cancer cells. A CD8+ T cell clone, recognising a peptide epitope derived from the ubiquitous Bax protein, was shown to recognise a broad range of tumour cells including primary CLL cells. We have developed techniques to isolate T cells recognising this epitope from both healthy donors and CLL patients. These T cells can be grown to large numbers and further studies exploring their therapeutic potential for CLL are in progress.

Immune suppression or tolerance

Generation of effective immune responses in cancer patients is hampered by T cell suppression or tolerance induced by cancer cells.

In collaboration with colleagues from Haematology, we have studied mechanisms of immune suppression using acute myeloid leukaemia (AML; Darley and Tonks) and chronic lymphocytic leukaemia (CLL; Pepper and Fegan). These studies identified an important role for CD200 in suppression of cellular immunity in AML. For CLL, we found that patients frequently demonstrated expansion in their CD8+ T cell subset . This caused an inversion in the CD4:CD8 ratio, and such patients had poorer clinical prognosis. The CD8+ T cells in CLL patients were enriched for terminally differentiated T cells, and for PD-1 expression, suggesting immune dysfunction. We are currently investigating the function and specificity of this expanded T cell subset, and the potential use of "T cell signatures" to identify patients who will develop aggressive disease. 

Unusual peptides recognised by CD8+ T-cells

Recently, we made the surprising finding that a human CD8+ T cell clone could recognise a synthetic peptide that had been modified by the addition of a tBu side chain (LLSY(3-tBu)FGTPT). Such tBu modifications do not occur in nature and their biological impact is unknown. Moreover the T cell clone failed to react against the corresponding unmodified wild type peptide (LLSYFGTPT). There was no discernible difference between the peptides in terms of binding to HLA-A2 molecules. Thus it appears that this T cell clone can discriminate between two peptides differing only by a single side-chain modification. We have recently obtained Wellcome Trust funding for a cross-disciplinary project that will involve collaboration between immunologists, peptide chemists and structural biologists. This project will address the following questions:

  1. What is the “natural” peptide ligand recognised by the T cell clone?
  2. What is the structural basis for recognition of the synthetic peptide?
  3. Can synthetic side-chain modifications modulate the function of CD8+ T cells?

Part of the project will involve solving crystal structures of at least 3 HLA-A2:peptide complexes, and examining the functional impact of modifications on CD8+ T cell function. The knowledge gained from this project could lead to the design of synthetic agents to boost or inhibit immune responses. 

Research Funding (last 5 years)

  • 2017 Cancer Research Wales. Studentship "The role of CD4+ T cell subsets in disease progression and response to treatment in CLL" £90,764 (PI)
  • 2015 Wellcome ISSF Cross-Disciplinary Award “Structural and functional impact of side-chain modification of peptides recognised by CD8+ T-cells” £40,000 (PI) 
  • 2015 Tenovus PhD Studentship “Are prostate stem cells susceptible to T cell-mediated killing?” £89,781 (CI with Dr Z.Tabi (PI)).
  • 2014 CRW Project Grant. “The function and clinical significance of CD4+ T cells in chronic lymphocytic leukaemia”   £44,502 (PI).
  • 2013 Leukaemia Lymphoma Research. “The role of tumour specific T cells in CLL”. £202,000 (PI)
  • 2012 Cardiff CR UK Centre. Development Fund Award £4671 (PI)
  • 2012 Cancer Research Wales. Studentship “ Role of CD8+ T cells in poor prognosis CLL”. £100,720. (PI)

I am interested in supervising PhD students in the following areas:

  • Cancer Immunology, in particular Leukaemia
  • Immunotherapy
  • Novel tumour antigens
  • Therapeutic cancer vaccines
  • Overcoming cancer associated immunosuppression
  • T cells as biomarkers for disease progression and/or response to treatment

Current supervision

Miss Amy Codd

Research student

Peter Henley

Research student

Mr Thomas Lewis

Research student

Past projects

Primary supervisor for Lauren Elston- Exploring the Role of CD8+ T Cells in Chronic Lymphocytic Leukaemia. PhD awarded April 2017. Currently a medical writer for the All Wales Therapeutics and Toxicology Centre.

Primary supervisor for Reiss Reid- Investigating the Role of T Cells in Chronic Lymphocytic Leukaemia. PhD awarded May 2015. Currently an investigator in Oncology Cell Therapy, GSK, Philadelphia USA. 

Primary supervisor for Ryan Wong- Breaking T cell tolerance in Chronic Lymphocytic Leukaemia. PhD awarded February 2013. Currently a Group Leader at Adaptimmune, Reading, UK.