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.
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.
Organisations
- CARDIFF UNIVERSITY (Lead Research Organisation)
- University College London (Collaboration)
- University Hospital of Wales (Collaboration)
- Heidelberg University Hospital (Collaboration)
- UNIVERSITY OF CAMBRIDGE (Collaboration)
- UNIVERSITY OF EDINBURGH (Collaboration)
- UNIVERSITY OF OXFORD (Collaboration)
- University of Pennsylvania (Collaboration)
- Cardiff University (Collaboration)
- National Institute of Allergy and Infectious Diseases (NIAID) (Collaboration)
- Eastern Virginia Medical School (Collaboration)
- Velindre Cancer Centre (Collaboration)
- Radboud University Nijmegen (Collaboration)
- Monash University (Collaboration)
Publications
Ager A
(2015)
Understanding high endothelial venules: Lessons for cancer immunology.
in Oncoimmunology
Ager A
(2016)
Homing to solid cancers: a vascular checkpoint in adoptive cell therapy using CAR T-cells.
in Biochemical Society transactions
Ager A
(2017)
High Endothelial Venules and Other Blood Vessels: Critical Regulators of Lymphoid Organ Development and Function.
in Frontiers in immunology
Bento D
(2015)
High endothelial venules are rare in colorectal cancers but accumulate in extra-tumoral areas with disease progression
in OncoImmunology
Brown LV
(2021)
Quantifying the limits of CAR T-cell delivery in mice and men.
in Journal of the Royal Society, Interface
Caucheteux SM
(2017)
Cytokine regulation of lung Th17 response to airway immunization using LPS adjuvant.
in Mucosal immunology
Cerretelli G
(2020)
Molecular pathology of Lynch syndrome
in The Journal of Pathology
Champion JD
(2022)
Drug Inhibition of Redox Factor-1 Restores Hypoxia-Driven Changes in Tuberous Sclerosis Complex 2 Deficient Cells.
in Cancers
Colbeck EJ
(2017)
Treg Depletion Licenses T Cell-Driven HEV Neogenesis and Promotes Tumor Destruction.
in Cancer immunology research
Colbeck EJ
(2017)
Tertiary Lymphoid Structures in Cancer: Drivers of Antitumor Immunity, Immunosuppression, or Bystander Sentinels in Disease?
in Frontiers in immunology
Crowther MD
(2020)
Genome-wide CRISPR-Cas9 screening reveals ubiquitous T cell cancer targeting via the monomorphic MHC class I-related protein MR1.
in Nature immunology
Demaria MC
(2020)
Tetraspanin CD53 Promotes Lymphocyte Recirculation by Stabilizing L-Selectin Surface Expression.
in iScience
Gawel-Beben K
(2018)
TMEFF2 shedding is regulated by oxidative stress and mediated by ADAMs and transmembrane serine proteases implicated in prostate cancer.
in Cell biology international
Hughes E
(2020)
Primary breast tumours but not lung metastases induce protective anti-tumour immune responses after Treg-depletion.
in Cancer immunology, immunotherapy : CII
Jones E
(2018)
Defining High Endothelial Venules and Tertiary Lymphoid Structures in Cancer.
in Methods in molecular biology (Clifton, N.J.)
Miles JJ
(2018)
Peptide mimic for influenza vaccination using nonnatural combinatorial chemistry.
in The Journal of clinical investigation
Mohammed RN
(2016)
L-selectin Is Essential for Delivery of Activated CD8(+) T Cells to Virus-Infected Organs for Protective Immunity.
in Cell reports
Mohammed RN
(2019)
ADAM17-dependent proteolysis of L-selectin promotes early clonal expansion of cytotoxic T cells.
in Scientific reports
O'Connor MN
(2021)
LRG1 destabilizes tumor vessels and restricts immunotherapeutic potency.
in Med (New York, N.Y.)
Ondondo B
(2014)
Progression of carcinogen-induced fibrosarcomas is associated with the accumulation of naïve CD4+ T cells via blood vessels and lymphatics.
in International journal of cancer
Ondondo B
(2015)
A distinct chemokine axis does not account for enrichment of Foxp3(+) CD4(+) T cells in carcinogen-induced fibrosarcomas.
in Immunology
Pfuderer PL
(2019)
High endothelial venules are associated with microsatellite instability, hereditary background and immune evasion in colorectal cancer.
in British journal of cancer
Seth S
(2018)
Lynch syndrome - cancer pathways, heterogeneity and immune escape.
in The Journal of pathology
Spary L
(2014)
Enhancement of T Cell Responses as a Result of Synergy between Lower Doses of Radiation and T Cell Stimulation
in The Journal of Immunology
Treps L
(2022)
Editorial: Tumor Vessels as Directors of the Tumor Microenvironment: New Findings, Current Challenges & Perspectives.
in Frontiers in cell and developmental biology
Watson HA
(2019)
L-Selectin Enhanced T Cells Improve the Efficacy of Cancer Immunotherapy.
in Frontiers in immunology
Watson HA
(2016)
Purity of transferred CD8(+) T cells is crucial for safety and efficacy of combinatorial tumor immunotherapy in the absence of SHP-1.
in Immunology and cell biology
Watson HA
(2016)
SHP-1: the next checkpoint target for cancer immunotherapy?
in Biochemical Society transactions
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 | 09/2017 |
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 | 09/2018 |
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 |
Amount | £21,571 (GBP) |
Organisation | GE Healthcare Limited |
Sector | Academic/University |
Country | United Kingdom |
Start | 07/2015 |
End | 08/2018 |
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 | 05/2015 |
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 | 08/2016 |
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 | 01/2019 |
End | 08/2023 |
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 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 | Hospitals |
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 | How COVID-19 vaccines work |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Public/other audiences |
Results and Impact | 60 healthcare workers and members of the public attended a webinar on How COVID-19 vaccines work given by Professor Ann Ager and organised by the Ethnic Minority Women in Welsh Healthcare and the Learned Society for Wales. his sparked a lot of questions and discussion afterwards and the organisers remoo |
Year(s) Of Engagement Activity | 2021 |
URL | https://1drv.ms/v/s!AmpVn1oRGgU1nEX7oBYeyRGWXmU_?e=AX6gu7 |
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 | Participated in I'm A Scientist Live - Health Zone |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Schools |
Results and Impact | The Health Zone ran from 2 to 27 November 2020. The Zone was one of 4 Zones that ran as part of I'm a Scientist: On Demand in November 2020. I'm a Scientist: On Demand aims to offer greater flexibility to teachers in how, and when, they can take part in I'm a Scientist. This is in response to the COVID-19 situation and greater restrictions and uncertainty in schools. The Health Zone was jointly funded by the Royal Society of Chemistry (RSC), and the British Society for Immunology (BSI). There were weekly evening chats for students to join from home, with two of these focussed on the topic of vaccinations. 50 scientists created profiles in the Zone. 10 reported being members of the RSC and 16 as members of the BSI. 48 scientists engaged with students through live Chats and/or Ask questions. Scientists were from a broad range of fields and career stages.#486 students from 23 schools all over the UK logged into the Zone. 42% of active students were from target schools (WP and/or U). 21% were from widening participation (WP) schools 21% were from underserved (U) schools. |
Year(s) Of Engagement Activity | 2020 |
URL | https://about.imascientist.org.uk/2021/health-zone-report-november-2020/ |
Description | Pint of Science - 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 | Tacking Cancer Together - Public and patient 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 | Interactive practical demonstration of T cell trafficking at 'Tackling Cancer Together' open day organised by the Wales Cancer Partnership, Cardiff, 25th November 2017 |
Year(s) Of Engagement Activity | 2017 |
URL | https://www.walescancerpartnership.com/partner-events/2017/11/25/tackling-cancer-together |
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 |