Dissecting the impact of L-selectin on T lymphocyte dependent tumour immunity

Lead Research Organisation: Cardiff University
Department Name: School of Medicine

Abstract

The harnessing of one's own immune system to treat a cancer, termed tumour immunotherapy, is an extremely attractive proposition because of the potential for combining high selectivity with low toxicity. Tumour immunotherapy has progressed significantly in recent years with improved understanding of how to boost the normally weak immune response to tumours. Nevertheless, there is considerable need for more improvements to ensure this form of treatment is more widely and effectively applied. Successful immunotherapy depends on immune cells, such as killer T lymphocytes, becoming activated and homing to the tumour. However, tumour blood vessels limit access of T lymphocytes to the tumour. We have found that T lymphocytes are better equipped to control tumour growth when they express the homing molecule L-selectin. We predict this is because L-selectin expression factilitates access of killer T cells to the tumour where they can deliver their lethal hit. The aim of this proposal is to study the properties of these L-selectin enhanced T lymphocytes and to determine whether they could be used to treat tumours. The potential long-term benefit of this work is that it will direct novel strategies for improving the clinical application of tumour immunotherapy.

Technical Summary

T lymphocyte infiltration of tumours correlates with improved outcome in patients. However, tumours actively suppress T cell recruitment by inhibiting the expression of homing associated cell adhesion molecules and chemokines on blood vessels in draining lymph nodes and within the tumour. The overall effect is to limit priming of T cells to tumour derived antigens in lymph nodes draining the tumour. Even if T cells are primed, recruitment into the tumour will be restricted because tumour blood vessels fail to support T lymphocyte homing. Strategies that boost the localisation of effector T cells capable of tumour destruction within the tumour may improve the efficacy of immunotherapies to control tumour growth. Several studies link the expression of the leucocyte specific homing molecule L-selectin/CD62L and tumour growth but the underlying mechanisms are unknown. Since L-selectin is an essential lymph node homing molecule, the role of L-selectin in regulating tumour immunity may be to facilitate T cell priming and differentiation in response to tumour derived antigens in draining lymph nodes. However, studies using L-selectin knockout mice have shown that reduced control of tumour growth in these mice is not simply due to lack of cytotoxic T lymphocyte (CTL) generation but correlated with a markedly reduced recruitment of leucocyes into the tumour. This highlights an important role for L-selectin in regulating leucocyte recruitment into tumours. We have found that the rapid growth of primary tumours in L-selectin deficient mice is reduced by maintaining expression of L-selectin on T lymphocytes. These data demonstrate that T cell expressed L-selectin controls tumour immunity and reveal a novel way of promoting tumour immunity by altering expression of homing molecules on T cells. The aim of this proposal is to study the properties of these L-selectin enhanced T lymphocytes and to determine whether they could be used to treat tumours.

Planned Impact

The cell adhesion molecules that regulate leucocyte recruitment from the bloodstream to sites of infection, immunity and inflammation are targets for immunotherapy but the idea of promoting immune responses by manipulating immune cell homing is relatively unexplored. This research will benefit academics and biotechnology industries interested in how immune responses are regulated by immune cell trafficking and provide training for postgraduate and postdoctoral science and medical students. It also has educational benefit to undergraduate and school students in understanding the complex interplay between the immune system and cancer. There is currently a lot of interest in the use of immunotherapy to control cancers and this research will be of general interest to the public.
Identification of strategies to improve the effectiveness of immunotherapies will contribute to improving the nation's health by combating chronic debilitating diseases such as cancer, autoimmunity and chonic infection. Training of Ph.D. students and post-doctoral scientists in leucocyte trafficking expands the expertise base within the UK and internationally. Participation in public lectures, open days for schools, work experience placements for school and undergraduate students from within the UK and Europe disseminates ongoing research in Cardiff into immunotherapy.

Publications

10 25 50
 
Description . Engineering homing properties of cancer-specfic T lymphocytes in adoptive cell therapy
Amount £9,000 (GBP)
Organisation Cardiff University 
Sector Academic/University
Country United Kingdom
Start 10/2017 
End 09/2020
 
Description BBSRC CASE Studentship
Amount £100,000 (GBP)
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 10/2018 
End 09/2022
 
Description Cancer Immunology Project Award
Amount £280,000 (GBP)
Funding ID C42412/A24416 
Organisation Cancer Research UK 
Sector Charity/Non Profit
Country United Kingdom
Start 11/2017 
End 10/2020
 
Description Longitudinal monitoring of T lymphocyte migration in vivo using Positron Emission Tomography-Computed tomography (PET-CT)
Amount £6,926 (GBP)
Organisation Cancer Research UK 
Sector Charity/Non Profit
Country United Kingdom
Start 06/2015 
End 06/2016
 
Description Preclinical models for novel immunotherapies using MHC restricted and non-restricted T-cells
Amount £80,000 (GBP)
Organisation Health and Care Research Wales 
Sector Public
Country United Kingdom
Start 09/2016 
End 08/2018
 
Description The regulation of protective immunity to viruses by L-selectin
Amount £557,898 (GBP)
Funding ID BB/S002480/1 
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 09/2018 
End 08/2021
 
Description HEV in cancer immunity 
Organisation University of Pennsylvania
Department School of Veterinary Medicine (UPenn)
Country United States 
Sector Academic/University 
PI Contribution Knowledge and critical appraisal of the research area
Collaborator Contribution Knowledge and critical appraisal of the research area.
Impact Publication in OncoImmunology
Start Year 2014
 
Description Immunity in inherited cancers 
Organisation Heidelberg University Hospital
Country Germany 
Sector Hospitals 
PI Contribution Academic background, technical expertise and critical appraisal of the field.
Collaborator Contribution Academic background, experimental data and critical appraisal of the field.
Impact None
Start Year 2017
 
Description Immunity in inherited cancers 
Organisation University Hospital of Wales
Department Institute of Medical Genetics
Country United Kingdom 
Sector Hospitals 
PI Contribution Knowledge and critical appraisal of the literature
Collaborator Contribution Knowledge and critical appraisal of the literature
Impact Publication in Journal of Pathology and discussions about collaborative research projects in the future.
Start Year 2017
 
Description Immunity in inherited cancers 
Organisation University of Edinburgh
Department Institute of Genetics & Molecular Medicine
Country United Kingdom 
Sector Academic/University 
PI Contribution Knowledge and critical appraisal of the literature.
Collaborator Contribution Knowledge and critical appraisal of the literature.
Impact Publication in Journal of Pathology and discussions about collaborative reseach projects for the future.
Start Year 2017
 
Description L-selectin in CD53 ko cells 
Organisation Radboud University Nijmegen
Country Netherlands 
Sector Academic/University 
PI Contribution Reagents and expertise. Critical appraisal of results.
Collaborator Contribution Experimental data and critical appraisal of the field of research.
Impact Manuscript in preparation.
Start Year 2017
 
Description L-selectin shedding 
Organisation Eastern Virginia Medical School
Country United States 
Sector Academic/University 
PI Contribution Experimental data, academic knowledge and critical appraisal.
Collaborator Contribution Experimental data.
Impact Manuscript submitted.
Start Year 2014
 
Description Low dose irradiation of T cells and cancer immunotherapy 
Organisation Velindre Cancer Centre
Country United Kingdom 
Sector Academic/University 
PI Contribution Determining the impact of low dose irradiation of T cells on adoptive cell therapy for solid cancers in experimental mice.
Collaborator Contribution Dr Zsuzsanni Tabi provided technical and practical assistance in the use of low dose irradiation of mouse T cells.
Impact Spary LK, Al-Taei S, Salimu J, Cook AD, Ager A, Watson HA, Clayton A, Staffurth J, Mason MD, Tabi Z. (2014) Enhancement of T cell responses as a result of synergy between lower doses of radiation and T cell stimulation. J Immunol. 192:3101-10; doi: 10.4049/jimmunol.1302736
Start Year 2014
 
Description Lung T cell responses to IL-1 and LPS 
Organisation National Institute of Allergy and Infectious Diseases (NIAID)
Department Laboratory of Immunology
Country United States 
Sector Public 
PI Contribution Analysis of the impact of LPS on pulmonary cytokine production and analysis of lung histology
Collaborator Contribution In depth analysis of cytokine and cellular responses in virus-infected and adjuvant challenged mouse lungs.
Impact Caucheteux S M, Hu-Li, Mohammed R, Ager A and Paul W E. Cytokine Regulation of Lung Th17 Response to Airway Immunization using LPS Adjuvant. (2016) Mucosal Immunol. doi: 10.1038/mi.2016.54
Start Year 2015
 
Description Membrane expression of L-selectin 
Organisation Monash University
Country Australia 
Sector Academic/University 
PI Contribution Reagents, techniques, academic background and critical appraisal of the field of research.
Collaborator Contribution Experimental data, academic background and critical appraisal of the field of research.
Impact Manuscript in preparation.
Start Year 2017
 
Description Metallproteinases and membrane protein shedding 
Organisation University of Cambridge
Department Department of Oncology
Country United Kingdom 
Sector Academic/University 
PI Contribution Experimental data, academic knowledge and critical appraisal.
Collaborator Contribution Reagents, academic knowledge and critical appraisal.
Impact Manuscript submitted.
Start Year 2014
 
Description Metallproteinases and membrane protein shedding 
Organisation University of Oxford
Department Kennedy Institute of Rheumatology
Country United Kingdom 
Sector Academic/University 
PI Contribution Experimental data, academic knowledge and critical appraisal.
Collaborator Contribution Reagents, academic knowledge and critical appraisal.
Impact Manuscript submitted.
Start Year 2014
 
Description T cell tracking by PET-CT 
Organisation Cardiff University
Department School of Medicine
Country United Kingdom 
Sector Academic/University 
PI Contribution Experimental models, practical expertise, academic background and critical appraisal of the field of research.
Collaborator Contribution Experimental and practical techniques, academic background and critical appraisal of the field of research.
Impact Manuscript submitted for publication.
Start Year 2017
 
Description Vascular normalisation and T cell therapy 
Organisation University College London
Department Institute of Ophthalmology UCL
Country United Kingdom 
Sector Academic/University 
PI Contribution Experimental data, academic background and critical appraisal of the field of research.
Collaborator Contribution Reagents, experimental data, academic background and critical appraisal of the field of research.
Impact None
Start Year 2017
 
Description Interview for Pythagorus' Trousers on Radio Cardiff 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Question and answer session in which Rhys Phillip questioned Dr Ann Ager about her recent findings related to combating virus infections. Broadcast in a weekly science and technology radio show on Radio Cardiff sponsored by Airbus Group.
Year(s) Of Engagement Activity 2016
 
Description L-selectin and anti-viral immunity 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Press release on 'Flu-tackling molecule found by Cardiff University scientists' was picked up by the BBC and displayed on BBC website.
Year(s) Of Engagement Activity 2016
URL http://www.bbc.co.uk/news/uk-wales-south-east-wales-35373730
 
Description Public outreach event 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Around 50 members of the public paid to attend a 'Pint of Science' event during which researchers talked about their research to the public and answered questions.
Year(s) Of Engagement Activity 2018
 
Description Science in Health live 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Schools
Results and Impact More than 800 year 12 pupils considering medicine and/or science careers attended a 2-day visit to participate in Science in Health-Live (SIH-L)organised by the School of Medicine, Cardiff University. It involves more than 150 members of staff, from postgraduates to Professors, who provide a diverse range of short talks, science theatre, stand-up comedy, a science quiz and interactive exhibits and laboratory tours. Dr Ager presented a lecture on 'Directing the traffic: how to leucocytes know where to go in the body?'
Throughout the day, interactive polling allows the students to text in questions they may have concerning entry to university, career prospects in science/medicine and individuals within the School respond to these questions. The closing event of the day profiles the careers of leading clinical and non-clinical investigators in which each investigator briefly explains how their science, education and personal interests have led them down distinct career paths. SIH Live aims to excite students about science by allowing them access to Cardiff University research that is having an impact upon medical and clinical practice worldwide. We further aim to inspire and inform secondary school students seeking career opportunities in biomedical science and medicine.Dr SIH Live aims to excite students about science by allowing them access to Cardiff University research that is having an impact upon medical and clinical practice worldwide. We further aim to inspire and inform secondary school students seeking career opportunities in biomedical science and medicine.
Year(s) Of Engagement Activity 2014
 
Description Soapbox Science 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Soapbox Science serves to bring cutting edge science to the public, in an accessible, fun and unintimidating way. Unlike other science events, the great thing about Soapbox Science is that the people you speak to will not have necessarily planned to come and learn about science and so you can inspire people who never normally get exposed to science, especially young people. Soapbox Science also gives female scientists the much-needed boost to their visibility and profile they need to help achieve equality in science.
Year(s) Of Engagement Activity 2017
URL https://www.cardiff.ac.uk/news/view/798209-soapbox-science-cardiff-2017
 
Description Ystradown WI 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Dr Ager gave a lay overview of her recent studies on 'T cells- a discovery' to 25 members of the Women's Institute int the area where she resides.
Year(s) Of Engagement Activity 2016